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<!doctype html> <html data-n-head-ssr lang="en" data-n-head="%7B%22lang%22:%7B%22ssr%22:%22en%22%7D%7D"> <head > <link data-n-head="ssr" rel="icon" type="image/png" sizes="16x16" href="https://brand.frontiersin.org/m/ed3f9ce840a03d7/favicon_16-tenantFavicon-Frontiers.png"> <link data-n-head="ssr" rel="icon" type="image/png" sizes="32x32" href="https://brand.frontiersin.org/m/ed3f9ce840a03d7/favicon_32-tenantFavicon-Frontiers.png"> <link data-n-head="ssr" rel="apple-touch-icon" type="image/png" sizes="180x180" href="https://brand.frontiersin.org/m/ed3f9ce840a03d7/favicon_180-tenantFavicon-Frontiers.png"> <title>Frontiers | Chondroitin Sulfate Alleviates Diabetic Osteoporosis and Repairs Bone Microstructure via Anti-Oxidation, Anti-Inflammation, and Regulating Bone Metabolism</title><meta data-n-head="ssr" charset="utf-8"><meta data-n-head="ssr" name="viewport" content="width=device-width, initial-scale=1"><meta data-n-head="ssr" data-hid="charset" charset="utf-8"><meta data-n-head="ssr" data-hid="mobile-web-app-capable" name="mobile-web-app-capable" content="yes"><meta data-n-head="ssr" data-hid="apple-mobile-web-app-title" name="apple-mobile-web-app-title" content="Frontiers | Articles"><meta data-n-head="ssr" data-hid="theme-color" name="theme-color" content="#0C4DED"><meta data-n-head="ssr" data-hid="description" property="description" name="description" content="Diabetic osteoporosis (DOP) belongs to secondary osteoporosis caused by diabetes; it has the characteristics of high morbidity and high disability. In the pr..."><meta data-n-head="ssr" data-hid="og:title" property="og:title" name="title" content="Frontiers | Chondroitin Sulfate Alleviates Diabetic Osteoporosis and Repairs Bone Microstructure via Anti-Oxidation, Anti-Inflammation, and Regulating Bone Metabolism"><meta data-n-head="ssr" data-hid="og:description" property="og:description" name="description" content="Diabetic osteoporosis (DOP) belongs to secondary osteoporosis caused by diabetes; it has the characteristics of high morbidity and high disability. In the pr..."><meta data-n-head="ssr" data-hid="keywords" name="keywords" content="chondroitin sulfate,diabetes,Osteoporosis,Bone microstructure,bone metabolism"><meta data-n-head="ssr" data-hid="og:site_name" property="og:site_name" name="site_name" content="Frontiers"><meta data-n-head="ssr" data-hid="og:image" property="og:image" name="image" content="https://images-provider.frontiersin.org/api/ipx/w=1200&f=png/https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g001.jpg"><meta data-n-head="ssr" data-hid="og:type" property="og:type" name="type" content="article"><meta data-n-head="ssr" data-hid="og:url" property="og:url" name="url" content="https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2021.759843/full"><meta data-n-head="ssr" data-hid="twitter:card" name="twitter:card" content="summary_large_image"><meta data-n-head="ssr" data-hid="citation_volume" name="citation_volume" content="12"><meta data-n-head="ssr" data-hid="citation_journal_title" name="citation_journal_title" content="Frontiers in Endocrinology"><meta data-n-head="ssr" data-hid="citation_publisher" name="citation_publisher" content="Frontiers"><meta data-n-head="ssr" data-hid="citation_journal_abbrev" name="citation_journal_abbrev" content="Front. Endocrinol."><meta data-n-head="ssr" data-hid="citation_issn" name="citation_issn" content="1664-2392"><meta data-n-head="ssr" data-hid="citation_doi" name="citation_doi" content="10.3389/fendo.2021.759843"><meta data-n-head="ssr" data-hid="citation_firstpage" name="citation_firstpage" content="759843"><meta data-n-head="ssr" data-hid="citation_language" name="citation_language" content="English"><meta data-n-head="ssr" data-hid="citation_title" name="citation_title" content="Chondroitin Sulfate Alleviates Diabetic Osteoporosis and Repairs Bone Microstructure via Anti-Oxidation, Anti-Inflammation, and Regulating Bone Metabolism"><meta data-n-head="ssr" data-hid="citation_keywords" name="citation_keywords" content="chondroitin sulfate; diabetes; Osteoporosis; Bone microstructure; bone metabolism"><meta data-n-head="ssr" data-hid="citation_abstract" name="citation_abstract" content="<p>Diabetic osteoporosis (DOP) belongs to secondary osteoporosis caused by diabetes; it has the characteristics of high morbidity and high disability. In the present study, we constructed a type 1 diabetic rat model and administered chondroitin sulfate (200 mg/kg) for 10 weeks to observe the preventive effect of chondroitin sulfate on the bone loss of diabetic rats. The results showed that chondroitin sulfate can reduce blood glucose and relieve symptoms of diabetic rats; in addition, it can significantly increase the bone mineral density, improve bone microstructure, and reduce bone marrow adipocyte number in diabetic rats; after 10 weeks of chondroitin sulfate administration, the SOD activity level was upregulated, as well as CAT levels, indicating that chondroitin sulfate can alleviate oxidative stress in diabetic rats. Chondroitin sulfate was also found to reduce the level of serum inflammatory cytokines (TNF-α, IL-1, IL-6, and MCP-1) and alleviate the inflammation in diabetic rats; bone metabolism marker detection results showed that chondroitin sulfate can reduce bone turnover in diabetic rats (decreased RANKL, CTX-1, ALP, and TRACP 5b levels were observed after 10 weeks of chondroitin sulfate administration). At the same time, the bone OPG and RUNX 2 expression levels were higher after chondroitin sulfate treatment, the bone RANKL expression was lowered, and the OPG/RANKL ratio was upregulated. All of the above indicated that chondroitin sulfate could prevent STZ-induced DOP and repair bone microstructure; the main mechanism was through anti-oxidation, anti-inflammatory, and regulating bone metabolism. Chondroitin sulfate could be used to develop anti-DOP functional foods and diet interventions for diabetes.</p>"><meta data-n-head="ssr" data-hid="citation_pdf_url" name="citation_pdf_url" content="https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2021.759843/pdf"><meta data-n-head="ssr" data-hid="citation_online_date" name="citation_online_date" content="2021/09/29"><meta data-n-head="ssr" data-hid="citation_publication_date" name="citation_publication_date" content="2021/10/27"><meta data-n-head="ssr" data-hid="citation_author_0" name="citation_author" content="Qi, Shan Shan"><meta data-n-head="ssr" data-hid="citation_author_institution_0" name="citation_author_institution" content="College of Food Science and Engineering, Northwest Agriculture and Forestry (A&F) University, China"><meta data-n-head="ssr" data-hid="citation_author_1" name="citation_author" content="Shao, Meng Li"><meta data-n-head="ssr" data-hid="citation_author_institution_1" name="citation_author_institution" content="College of Biological Science and Engineering, Shaanxi University of Technology, China"><meta data-n-head="ssr" data-hid="citation_author_2" name="citation_author" content="Sun, Ze"><meta data-n-head="ssr" data-hid="citation_author_institution_2" name="citation_author_institution" content="College of Biological Science and Engineering, Shaanxi University of Technology, China"><meta data-n-head="ssr" data-hid="citation_author_3" name="citation_author" content="Chen, Si Min"><meta data-n-head="ssr" data-hid="citation_author_institution_3" name="citation_author_institution" content="College of Biological Science and Engineering, Shaanxi University of Technology, China"><meta data-n-head="ssr" data-hid="citation_author_4" name="citation_author" content="Hu, Ying Jun"><meta data-n-head="ssr" data-hid="citation_author_institution_4" name="citation_author_institution" content="College of Biological Science and Engineering, Shaanxi University of Technology, China"><meta data-n-head="ssr" data-hid="citation_author_5" name="citation_author" content="Li, Xin Sheng"><meta data-n-head="ssr" data-hid="citation_author_institution_5" name="citation_author_institution" content="College of Biological Science and Engineering, Shaanxi University of Technology, China"><meta data-n-head="ssr" data-hid="citation_author_6" name="citation_author" content="Chen, De Jing"><meta data-n-head="ssr" data-hid="citation_author_institution_6" name="citation_author_institution" content="College of Biological Science and Engineering, Shaanxi University of Technology, China"><meta data-n-head="ssr" data-hid="citation_author_7" name="citation_author" content="Zheng, Hong Xing"><meta data-n-head="ssr" data-hid="citation_author_institution_7" name="citation_author_institution" content="College of Biological Science and Engineering, Shaanxi University of Technology, China"><meta data-n-head="ssr" data-hid="citation_author_8" name="citation_author" content="Yue, Tian Li"><meta data-n-head="ssr" data-hid="citation_author_institution_8" name="citation_author_institution" content="College of Food Science and Engineering, Northwest Agriculture and Forestry (A&F) University, China"><meta data-n-head="ssr" data-hid="dc.identifier" name="dc.identifier" content="doi:10.3389/fendo.2021.759843"><link data-n-head="ssr" rel="manifest" href="/article-pages/_nuxt/manifest.c499fc0a.json" data-hid="manifest"><link data-n-head="ssr" rel="canonical" href="https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2021.759843/full"><script data-n-head="ssr" data-hid="newrelic-browser-script" type="text/javascript">window.NREUM||(NREUM={});NREUM.info = {"agent":"","beacon":"bam.nr-data.net","errorBeacon":"bam.nr-data.net","licenseKey":"598a124f17","applicationID":"588603994","agentToken":null,"applicationTime":2.806207,"transactionName":"MQcDMkECCkNSW0YMWghNIgldDQFTRxd1IGFJTQ==","queueTime":0,"ttGuid":"cc761c4f97941629"}; (window.NREUM||(NREUM={})).init={privacy:{cookies_enabled:true},ajax:{deny_list:["bam.nr-data.net"]},distributed_tracing:{enabled:true}};(window.NREUM||(NREUM={})).loader_config={agentID:"594400880",accountID:"230385",trustKey:"230385",xpid:"VgUHUl5WGwYIXFdSBAgOUg==",licenseKey:"598a124f17",applicationID:"588603994"};;/*! 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office</a></li></ul></div></div></div> <div class="Ibar__spacer"></div> <a href="https://www.frontiersin.org/submission/submit?domainid=2&fieldid=23&specialtyid=0&entitytype=2&entityid=106" data-event="iBarJournal-a-submit" class="Ibar__button Ibar__submit"><span>Submit</span> <span> your research</span></a> <a href="/search" aria-label="Search" data-event="iBar-a-search" class="Ibar__icon Ibar__icon--search"><span>Search</span></a>    <div class="Ibar__userArea"></div></div></div></nav> <div class="ArticlePage"><div><div class="Layout Layout--withAside Layout--withIbarMix ArticleDetails"> <main class="Layout__main"> <div class="ArticleDetails__main"><div class="ArticleLayoutHeader"><div class="ArticleLayoutHeader__info"><p class="ArticleLayoutHeader__info__title"> ORIGINAL RESEARCH article </p> <p class="ArticleLayoutHeader__info__journalDate"><span>Front. Endocrinol.</span> <span>, 27 October 2021</span></p> <p class="ArticleLayoutHeader__info__journalDate"> Sec. Clinical Diabetes </p> <p class="ArticleLayoutHeader__info__doiVolume"><span> Volume 12 - 2021 | </span> <a href="https://doi.org/10.3389/fendo.2021.759843" class="ArticleLayoutHeader__info__doi"> https://doi.org/10.3389/fendo.2021.759843 </a></p> </div>  <p class="ArticleLayoutHeader__isPartOfRT"><span class="ArticleLayoutHeader__isPartOfRT__label">This article is part of the Research Topic</span> <span class="ArticleLayoutHeader__isPartOfRT__title">Diabetes and Bone - From Cell to Human</span> <span class="Link__wrapper"><a aria-label="View all 11 articles" href="https://www.frontiersin.org/research-topics/23162/diabetes-and-bone---from-cell-to-human/articles" target="_self" data-event="customLink-link-a_viewAll11Articles" class="Link Link--linkType Link--maincolor Link--medium Link--icon Link--chevronRight Link--right"><span>View all 11 articles</span></a></span></p></div> <div class="ArticleDetails__main__content"><div class="ArticleDetails__main__content__main ArticleDetails__main__content__main--fullArticle"><div class="JournalAbstract"><div class="JournalAbstract__titleWrapper"><h1>Chondroitin Sulfate Alleviates Diabetic Osteoporosis and Repairs Bone Microstructure <i>via</i> Anti-Oxidation, Anti-Inflammation, and Regulating Bone Metabolism</h1> </div> </div> <div class="JournalFullText"><div class="JournalAbstract"><a id="h1" name="h1"></a><div class="authors"><span class="author-wrapper notranslate"><a href="https://loop.frontiersin.org/people/889583" class="user-id-889583"><img class="pr5" src="https://loop.frontiersin.org/images/profile/889583/74" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';" alt="Shan Shan Qi,,">Shan Shan Qi</a><sup>1,2,3</sup></span><span class="author-wrapper notranslate"><img class="pr5" src="https://loop.frontiersin.org/cdn/images/profile/default_32.jpg" alt="Meng Li Shao," onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';">Meng Li Shao<sup>2,3</sup></span><span class="author-wrapper notranslate"><img class="pr5" src="https://loop.frontiersin.org/cdn/images/profile/default_32.jpg" alt="Ze Sun," onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';">Ze Sun<sup>2,4</sup></span><span class="author-wrapper notranslate"><img class="pr5" src="https://loop.frontiersin.org/cdn/images/profile/default_32.jpg" alt="Si Min Chen" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';">Si Min Chen<sup>2</sup></span><span class="author-wrapper notranslate"><img class="pr5" src="https://loop.frontiersin.org/cdn/images/profile/default_32.jpg" alt="Ying Jun Hu" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';">Ying Jun Hu<sup>2</sup></span><span class="author-wrapper notranslate"><img class="pr5" src="https://loop.frontiersin.org/cdn/images/profile/default_32.jpg" alt="Xin Sheng Li," onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';">Xin Sheng Li<sup>2,5</sup></span><span class="author-wrapper notranslate"><img class="pr5" src="https://loop.frontiersin.org/cdn/images/profile/default_32.jpg" alt="De Jing Chen,*" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';">De Jing Chen<sup>2,3*</sup></span><span class="author-wrapper notranslate"><a href="https://loop.frontiersin.org/people/1397318" class="user-id-1397318"><img class="pr5" src="https://loop.frontiersin.org/images/profile/1397318/74" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';" alt="Hong Xing Zheng,,*">Hong Xing Zheng</a><sup>2,3,5*</sup></span><span class="author-wrapper notranslate"><img class="pr5" src="https://loop.frontiersin.org/cdn/images/profile/default_32.jpg" alt="Tian Li Yue,*" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';">Tian Li Yue<sup>1,6*</sup></span></div><ul class="notes"><li><span><sup>1</sup></span>College of Food Science and Engineering, Northwest Agriculture and Forestry (A&F) University, Yangling, China</li><li><span><sup>2</sup></span>College of Biological Science and Engineering, Shaanxi University of Technology, Hanzhong, China</li><li><span><sup>3</sup></span>Qinba State Key Laboratory of Biological Resources and Ecological Environment, Hanzhong, China</li><li><span><sup>4</sup></span>QinLing-Bashan Mountains Bioresources Comprehensive Development C.I.C., Hanzhong, China</li><li><span><sup>5</sup></span>Shaanxi Key Laboratory of Resource Biology, Hanzhong, China</li><li><span><sup>6</sup></span>College of Food Science and Technology, Northwest University, Xi’an, China</li></ul><p>Diabetic osteoporosis (DOP) belongs to secondary osteoporosis caused by diabetes; it has the characteristics of high morbidity and high disability. In the present study, we constructed a type 1 diabetic rat model and administered chondroitin sulfate (200 mg/kg) for 10 weeks to observe the preventive effect of chondroitin sulfate on the bone loss of diabetic rats. The results showed that chondroitin sulfate can reduce blood glucose and relieve symptoms of diabetic rats; in addition, it can significantly increase the bone mineral density, improve bone microstructure, and reduce bone marrow adipocyte number in diabetic rats; after 10 weeks of chondroitin sulfate administration, the SOD activity level was upregulated, as well as CAT levels, indicating that chondroitin sulfate can alleviate oxidative stress in diabetic rats. Chondroitin sulfate was also found to reduce the level of serum inflammatory cytokines (TNF-α, IL-1, IL-6, and MCP-1) and alleviate the inflammation in diabetic rats; bone metabolism marker detection results showed that chondroitin sulfate can reduce bone turnover in diabetic rats (decreased RANKL, CTX-1, ALP, and TRACP 5b levels were observed after 10 weeks of chondroitin sulfate administration). At the same time, the bone OPG and RUNX 2 expression levels were higher after chondroitin sulfate treatment, the bone RANKL expression was lowered, and the OPG/RANKL ratio was upregulated. All of the above indicated that chondroitin sulfate could prevent STZ-induced DOP and repair bone microstructure; the main mechanism was through anti-oxidation, anti-inflammatory, and regulating bone metabolism. Chondroitin sulfate could be used to develop anti-DOP functional foods and diet interventions for diabetes.</p><div class="clear"></div></div><div class="JournalFullText"><a id="h2" name="h2"></a><h2>Introduction</h2><p class="mb15">There are 463 million people with diabetes worldwide currently, an average of 1 in 11 adults (20–79 years old), and by 2045, the diabetes population will jump to 700 million (<a href="#B1">1</a>, <a href="#B2">2</a>). Long-term high blood glucose can cause microvascular injury, endangering the kidneys, heart, eyes, peripheral nerves, brain, feet, as well as bone (<a href="#B3">3</a>).</p><p class="mb15">Diabetic osteoporosis (DOP) is a bone complication caused by diabetes, characterized by lowered bone mineral density (BMD), changes of bone microstructure, and raised bone fragility. DOP greatly reduces the quality of living of patients, subjecting them to heavy economic burden (<a href="#B4">4</a>). As the number of people with diabetes increases globally, the number of DOP is also increasing annually. Clinical data showed that about 50% to 65% of people with diabetes have decreased BMD and increased incidence of fractures, and nearly 35% of them have been diagnosed as osteoporosis (<a href="#B5">5</a>).</p><p class="mb15">The present approaches for DOP are oral hypoglycemic drugs or insulin injections, supplemented by calcium preparations, bisphosphonates, etc. (<a href="#B6">6</a>). However, adverse drug reactions have always been a major challenge related to drug treatment goals. Therefore, exploring more safer and effective strategies are highly crucial.</p><p class="mb0">Chondroitin sulfate (CS) is a natural sticky polysaccharide made from the cartilage of animals. The content of CS is different in the cartilage of different species and ages. As a drug for the treatment of joint diseases, it was used in conjunction with glucosamine to relieve pain and promote cartilage regeneration, which can fundamentally improve joint problems (<a href="#B7">7</a>). It was reported that CS has anti-inflammation effects (<a href="#B8">8</a>), has anti-psoriasis effects (<a href="#B9">9</a>), enhances immunity (<a href="#B10">10</a>), lowers blood lipid (<a href="#B11">11</a>), and has anti-tumor effects (<a href="#B12">12</a>). It also has a preventive effect on diabetic nephropathy.in streptozotocin (STZ)-induced diabetic mice (<a href="#B13">13</a>), and CS was also reported to increase bone formation in ovariectomized rats (<a href="#B14">14</a>). Whether it has a protective effect on DOP has not been studied. Our previous study found that the CS could increase the BMD of diabetic rats, but the mechanisms were not clear. So, in present study, we researched the protective effect and mechanisms of CS on DOP, which will provide a new approach for DOP treatment.</p><a id="h3" name="h3"></a><h2>Materials and Methods</h2><h3>Chemicals</h3><p class="mb0">CS power was isolated and purified from the cartilage of giant salamander according to the method of Zhu (<a href="#B15">15</a>); the content of CS in the experimental materials was 95%. STZ was obtained from Acmec Biochemical Company (Shanghai, China).</p><h3>Animals</h3><p class="mb0">Fifty-six-day old male rats were obtained from Cheng Du Dashuo Experimental Animal Company (Cheng Du, China, license no. SCXK 2020-030). Animals were kept in independent ventilated cages in a standardized animal room with constant temperature and humidity. Water and food intake of animals was not restricted. Animals were feed with diets prepared by the American Society of Nutrition (AIN93) standard. Animal experiment operations were approved by Shaanxi University of Technology Animal Ethics Committee (approval No. 2020-74).</p><h3>Diabetes Induction in SD Rats, Animal Grouping, and Treatment</h3><p class="mb15">After 7 days of acclimatization, except for 10 animals in the control group, the remaining animals were intraperitoneally injected with 45 mg/kg of STZ after fasting overnight, and the dosage of STZ was based on our previous study (<a href="#B16">16</a>, <a href="#B17">17</a>); STZ was dissolved in citric acid buffer solution at pH 4.3, and 10 animals in the control group were injected with citric acid buffer solution. After 72 h, animal’s blood glucose was detected, and animals with blood glucose higher than 11.1 mmol/L were selected for subsequent experiments.</p><p class="mb15">Then, animals were regrouped into four groups: Group 1, control group (<i>n</i> = 10), rats were given deionized water by gavage every day; Group 2, type 1 diabetic group (<i>n</i> = 10), named T1DM group, type 1 diabetic rats were given deionized water by gavage every day; Group 3, CS-treated group (<i>n</i> = 10), named CS group, type 1 diabetic rats were given CS (200 mg/kg/day) by gavage every day; Group 4, metformin group (<i>n</i> = 10), named Met group, type 1 diabetic rats were given metformin (200 mg/kg/day) by gavage every day. The dose of CS was selected by pre-experiment.</p><p class="mb0">During the experiment, animals were weighed every week, water and diet of animals were recorded, and the blood glucose of animals was measured every week. After 10 weeks of administration, animals were anesthetized with isoflurane and were sacrificed by cervical dislocation; blood was collected, and serum was separated and stored at −80°C. At the same time, femurs, vertebrae, and tibias of animals were collected.</p><h3>BMD Measurement</h3><p class="mb0">The BMD of femur and vertebrae of each rat were obtained by using small-animal dual-energy X-ray absorptiometry (InAlzyer, Korea).</p><h3>Bone Micro-CT Measurement</h3><p class="mb0">Femur tissues of rats were collected and scanned by a Locus SP micro-CT (GE Healthcare, Danderyd, Sweden) with a resolution of 6.5μm. The processing and analysis software were MICVIEW 3D reconstruction processing software and ABA-specific bone analysis software. The data of cortex volume, bone surface area, trabecular number, and bone volume were obtained by using ABA-specific bone analysis software.</p><h3>Bone Turnover Marker Detection</h3><p class="mb0">According to instructions listed in ELISA test kits (Elabscience, Wuhan, China), a microplate reader (Elx808, Winooski, USA) was used to detect the content of bone turnover markers (CTX-1, OPG, ALP, TRACP 5b, RANKL, osteocalcin, and RUNX 2) in serum of each group of rats.</p><h3>Oxidative Stress Index Detection</h3><p class="mb0">According to instructions listed in kits (Beyotime, Shanghai, China), SOD activity, MDA content, CAT activity, and GSH content in serum were detected by an ultraviolet and visible spectrophotometer (Alpha1860S, Shanghai, China).</p><h3>Inflammatory Cytokine Detection</h3><p class="mb0">Based on instructions listed in ELISA test kits (Elabscience, Wuhan, China), the microplate reader (Elx808, Winooski, USA) was used to detect the content of serum inflammatory cytokines (IL-6, TNF-α, MCP-1, and IL-1).</p><h3>Pathological Analysis of Femur Bone Tissue</h3><p class="mb0">Femur of each rat was fixed in 3.8% paraformaldehyde solution for 48 h, then rinsed with PBS, placed in 10% EDTA solution for 5 weeks, and then made into 4-micron-thick paraffin sections by a tissue slicer (Leica, Wetzlar, Germany), and the sections were stained with hematoxylin and eosin, sealed with neutral gum. After that, a slide was placed under a microscope to observe femur pathological changes. Bone morphometric parameters including trabecular separation (Tb·Sp), bone volume per tissue volume (BV/TV), and trabecular thickness (Tb·Th) were analyzed by image pro plus (IPP) 6.0 software.</p><h3>Pathological Observation of Tibia Bone Marrow Adipocytes</h3><p class="mb0">Tibia of each rat was fixed in 3.8% paraformaldehyde solution for 48 h, then rinsed with PBS; femur was placed in 10% EDTA solution for 5 weeks and then made into 4-micron-thick paraffin sections by a tissue slicer (Leica, Wetzlar, Germany), and sections were stained with hematoxylin and eosin, sealed with neutral gum. After that, the slide was placed under a microscope to observe bone marrow adipocytes in tibia. Adipocytes were counted in each field, and the diameter of adipocytes was measured with IPP 6.0 software.</p><h3>Femur Osteoclast Observation-TRAP Staining</h3><p class="mb0">Four-micron-thick femur paraffin sections were stained with TRAP staining kit, based on the instructions listed in the kit. The stained slides were sealed with neutral gum. After that, a slide was placed under a microscope (200× magnification) to observe osteoclasts in the femur. Osteoclasts were purple-red after staining, five fields of view were selected for each slice, and the number of osteoclasts in each field was counted.</p><h3>Immunohistochemical</h3><p class="mb0">Femur paraffin slides (4 μm thick) were soaked in xylene for 20 min, and then slides were dehydrated with gradient ethanol and placed in a water bath at 95°C in citrate antigen retrieval solution (pH 6) for 1 h. After cooling to room temperature, slides were washed with PBS; 1% BSA solution was added to the slides to block endogenous peroxidase, and then the slides were washed with PBS, incubated with primary antibodies (OPG, RANKL, and RUNX2, respectively) (Santa Cruz Biotech, USA) for 1.5 h at 37°C in a constant temperature incubator, double washed with PBS, incubated with secondary antibody (Santa Cruz Biotech, USA) for 2 h, washed with PBS three times, and then incubated with DAB. After that, slides were counterstained with hematoxylin, and sealed with neutral gum. IHC-stained slides were observed under a microscope (Olympus, Germany) with 200× magnification. Five fields of view were chosen for each slice, and IPP software was used to count the area of positive staining, and percentage of positive area was calculated.</p><h3>Statistical Analysis</h3><p class="mb0">Statistical analyses were performed with ANOVA by SPASS 19.0; all of the data were shown as mean ± SD, and statistical significance was compared between groups using the LSD method. <i>p</i> < 0.05 was considered significant, and <i>p</i> < 0.01 was considered extremely significant.</p><a id="h4" name="h4"></a><h2>Results</h2><h3>Chondroitin Sulfate Relieved the Symptoms of Hyperglycemia, Polydipsia, and Polyphagia Caused by Diabetes in SD Rats</h3><p class="mb0">The blood glucose, water intake, and food intake in type 1 diabetic rats were significantly increased compared with control (<i>p</i> < 0.01) (<a href="#f1">Figures 1A, C, D</a>), while the body weight was decreased (<a href="#f1">Figure 1B</a>); this result was consistent with basic pathological changes of diabetes, indicating that the type 1 diabetes animal model was successfully established. After 10 weeks of CS or metformin administration, the symptoms of diabetes in rats were effectively alleviated, reflected in lowered blood glucose, increased body weight, and reduced water and food intake. This indicates that CS can reduce blood glucose of diabetic rats and relieve the symptoms of diabetes.</p><div class="DottedLine"></div><div class="Imageheaders">FIGURE 1</div><div class="FigureDesc"><a href="https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g001.jpg" name="" target="_blank"> <picture> <source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=480&f=webp/https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g001.jpg" media="(max-width: 563px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=370&f=webp/https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g001.jpg" media="(max-width: 1024px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=290&f=webp/https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g001.jpg" media="(max-width: 1441px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=410&f=webp/https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g001.jpg" media=""><source type="image/jpg" srcset="https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g001.jpg" media=""> <img src="https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g001.jpg" alt="www.frontiersin.org" id="f1" loading="lazy"> </picture> </a><p><strong>Figure 1</strong> Blood glucose, body weight, food intake, and water intake at the end of the 10th week in different groups. <strong>(A)</strong> Blood glucose in different groups. <strong>(B)</strong> Body weight in different groups. <strong>(C)</strong> Food intake in different groups. <strong>(D)</strong> Water intake in different groups. <sup>##</sup>indicates <i>p</i> < 0.01 compared with control; **indicates <i>p</i> < 0.01 compared with the diabetic group; *indicates <i>p</i> < 0.05 compared with the diabetic group.</p></div><div class="DottedLine"></div><h3>Chondroitin Sulfate Increased BMD of Type 1 Diabetic Rats</h3><p class="mb0">Compared with control group, the BMD (lumbar vertebrae and femur) in diabetic rats was lowered significantly (<i>p</i> < 0.01) (<a href="#f2">Figure 2</a>). After 10 weeks of CS or metformin administration, the BMD in lumbar vertebrae and femur was increased (CS <i>vs</i>. T1DM group, <i>p</i> < 0.01; Metformin <i>vs</i>. T1DM groups, <i>p</i> < 0.01) (<a href="#f2">Figure 2</a>), indicating that CS could increase the BMD of type 1 diabetic rats.</p><div class="DottedLine"></div><div class="Imageheaders">FIGURE 2</div><div class="FigureDesc"><a href="https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g002.jpg" name="" target="_blank"> <picture> <source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=480&f=webp/https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g002.jpg" media="(max-width: 563px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=370&f=webp/https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g002.jpg" media="(max-width: 1024px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=290&f=webp/https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g002.jpg" media="(max-width: 1441px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=410&f=webp/https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g002.jpg" media=""><source type="image/jpg" srcset="https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g002.jpg" media=""> <img src="https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g002.jpg" alt="www.frontiersin.org" id="f2" loading="lazy"> </picture> </a><p><strong>Figure 2</strong> The bone mineral density of different groups at the end of the 10th week. <strong>(A)</strong> The BMD of lumbar vertebrae in different groups. <strong>(B)</strong> The femoral BMD in different groups. <sup>##</sup>indicates <i>p</i> < 0.01 compared with control. **indicates <i>p</i> < 0.01 compared with the diabetic group.</p></div><div class="DottedLine"></div><h3>Chondroitin Sulfate Repaired Bone Micro-CT Structure of Type 1 Diabetic Rats</h3><p class="mb0">Femur micro-CT scanning results showed that trabecular structure in the model group was sparse, and some trabecular areas disappeared (<a href="#f3">Figure 3A</a>). After 10 weeks of administration of CS or metformin, trabecular structure was repaired. Micro-CT metrological data (<a href="#f3">Figures 3A–E</a>) showed that cortical bone volume, bone surface area, number of bone trabecular, and bone volume in type 1 diabetic group were significantly lower than those in the control group (<i>p</i> < 0.01). After 10 weeks of CS or metformin administration, the above indexes were upregulated, and the differences were significant compared with the diabetic group.</p><div class="DottedLine"></div><div class="Imageheaders">FIGURE 3</div><div class="FigureDesc"><a href="https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g003.jpg" name="" target="_blank"> <picture> <source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=480&f=webp/https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g003.jpg" media="(max-width: 563px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=370&f=webp/https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g003.jpg" media="(max-width: 1024px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=290&f=webp/https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g003.jpg" media="(max-width: 1441px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=410&f=webp/https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g003.jpg" media=""><source type="image/jpg" srcset="https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g003.jpg" media=""> <img src="https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g003.jpg" alt="www.frontiersin.org" id="f3" loading="lazy"> </picture> </a><p><strong>Figure 3</strong> <strong>(A)</strong> The femur micro-CT structure of different groups at the end of the 10th week. <strong>(B)</strong> Cortex volume in different groups. <strong>(C)</strong> Bone surface area in different groups. <strong>(D)</strong> Trabecular number in different groups. <strong>(E)</strong> Bone volume in different groups. <sup>##</sup>indicates <i>p</i> < 0.01 compared with control. **indicates <i>p</i> < 0.01 compared with the diabetic group.</p></div><div class="DottedLine"></div><h3>Chondroitin Sulfate Regulated Bone Turnover of Type 1 Diabetic Rats</h3><p class="mb0">As <a href="#T1">Table 1</a> shows, some of the serum bone turnover markers (OPG, RUNX 2, osteocalcin, and TRACP 5b) and OPG/RANKL ratio levels were lowered in type 1 diabetic rats compared with control (<i>p</i> < 0.01), and those were significantly increased in the CS and Met group compared with the type 1 diabetic group. Other serum bone turnover markers such as RANKL, CTX 1, and ALP levels were higher in the type 1 diabetic group compared with the control (<i>p</i> < 0.01), which were significantly decreased in CS and Met groups, indicating that CS could regulate bone turnover of type 1 diabetic rats.</p><div class="DottedLine"></div><div class="Imageheaders">TABLE 1</div><div class="FigureDesc"><a href="https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-t001.jpg" name="table 1" target="_blank"> <picture> <source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=480&f=webp/https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-t001.jpg" media="(max-width: 563px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=370&f=webp/https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-t001.jpg" media="(max-width: 1024px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=290&f=webp/https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-t001.jpg" media="(max-width: 1441px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=410&f=webp/https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-t001.jpg" media=""><source type="image/jpg" srcset="https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-t001.jpg" media=""> <img src="https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-t001.jpg" alt="www.frontiersin.org" id="T1" loading="lazy"> </picture> </a><p><strong>Table 1</strong> Bone turnover markers in different groups at the end of the 10th week.</p></div><div class="DottedLine"></div><h3>Chondroitin Sulfate Downregulated Inflammatory Cytokines of Type 1 Diabetic Rats</h3><p class="mb0">Serum inflammatory cytokine levels in type 1 diabetic rats increased dramatically compared with the control group (<i>p</i> < 0.01). After 10 weeks of CS or metformin treatment, the serum inflammatory cytokine levels were lowered in CS or Met groups (CS <i>vs</i>. T1DM group, <i>p</i> < 0.01; Metformin <i>vs</i>. T1DM groups, <i>p</i> < 0.01) (<a href="#f4">Figure 4</a>), indicating that CS has an inhibitory effect on inflammation induced by type 1 diabetes in SD rats.</p><div class="DottedLine"></div><div class="Imageheaders">FIGURE 4</div><div class="FigureDesc"><a href="https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g004.jpg" name="" target="_blank"> <picture> <source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=480&f=webp/https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g004.jpg" media="(max-width: 563px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=370&f=webp/https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g004.jpg" media="(max-width: 1024px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=290&f=webp/https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g004.jpg" media="(max-width: 1441px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=410&f=webp/https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g004.jpg" media=""><source type="image/jpg" srcset="https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g004.jpg" media=""> <img src="https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g004.jpg" alt="www.frontiersin.org" id="f4" loading="lazy"> </picture> </a><p><strong>Figure 4</strong> The serum inflammatory cytokine levels in different groups at the end of the 10th week. <strong>(A)</strong> MCP-1 levels in serum; <strong>(B)</strong> IL-6 levels in serum; <strong>(C)</strong> IL-1 levels in serum; <strong>(D)</strong> TNF-a levels in serum. <sup>##</sup>indicates <i>p</i> < 0.01 compared with control. **indicates <i>p</i> < 0.01 compared with the diabetic group.</p></div><div class="DottedLine"></div><h3>Chondroitin Sulfate Alleviated Oxidative Stress in Type 1 Diabetic Rats</h3><p class="mb0">Oxidative stress existed in diabetic rats; serum SOD, GPX, and CAT activity levels were lowered, and MDA level was raised in type 1 diabetic rats. Ten weeks after CS or metformin treatment, SOD, GPX, and CAT activity levels were raised, and MDA level was lowered (CS <i>vs</i>. T1DM, <i>p</i> < 0.01; Met <i>vs</i>. T1DM, <i>p</i> < 0.01) (<a href="#f5">Figure 5</a>). The results indicated that CS could alleviate oxidative stress in T1DM rats.</p><div class="DottedLine"></div><div class="Imageheaders">FIGURE 5</div><div class="FigureDesc"><a href="https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g005.jpg" name="" target="_blank"> <picture> <source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=480&f=webp/https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g005.jpg" media="(max-width: 563px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=370&f=webp/https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g005.jpg" media="(max-width: 1024px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=290&f=webp/https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g005.jpg" media="(max-width: 1441px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=410&f=webp/https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g005.jpg" media=""><source type="image/jpg" srcset="https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g005.jpg" media=""> <img src="https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g005.jpg" alt="www.frontiersin.org" id="f5" loading="lazy"> </picture> </a><p><strong>Figure 5</strong> The level of serum oxidative stress parameters in different groups at the end of the 10th week. <strong>(A)</strong> The level of SOD activities in different groups. <strong>(B)</strong> The level of glutathione peroxidase (GPX) activities in different groups. <strong>(C)</strong> The level of catalase (CAT) activities in different groups. <strong>(D)</strong> The level of malondialdehyde (MDA) content in different groups; <sup>##</sup>indicates <i>p</i> < 0.01 compared with control, **indicates <i>p</i> < 0.01 compared with the diabetic group.</p></div><div class="DottedLine"></div><h3>Chondroitin Sulfate Repaired Bone Microstructure of Type 1 Diabetic Rats</h3><p class="mb0">Compared with the control group, the femoral bone of diabetic rats was sparse and fractured, the spacing of trabecular bone became wider, and the trabecular bone became thinner (<a href="#f6">Figures 6A–D</a>). The femoral structure was repaired after 10 weeks of CS or metformin administration. The results of bone morphometric data (<a href="#f6">Figures 6E–G</a>) showed that the femoral thickness (Tb·Th) and the percentage of bone trabecular area (BV/TV) in CS or metformin treatment groups were significantly increased compared with the type 1 diabetic group (<i>p</i> < 0.01), and the trabecular separation (Tb·Sp) was decreased in CS or metformin treatment groups compared with the type 1 diabetic group (<i>p</i> < 0.01).</p><div class="DottedLine"></div><div class="Imageheaders">FIGURE 6</div><div class="FigureDesc"><a href="https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g006.jpg" name="" target="_blank"> <picture> <source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=480&f=webp/https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g006.jpg" media="(max-width: 563px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=370&f=webp/https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g006.jpg" media="(max-width: 1024px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=290&f=webp/https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g006.jpg" media="(max-width: 1441px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=410&f=webp/https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g006.jpg" media=""><source type="image/jpg" srcset="https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g006.jpg" media=""> <img src="https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g006.jpg" alt="www.frontiersin.org" id="f6" loading="lazy"> </picture> </a><p><strong>Figure 6</strong> The pathological sections of femur of rats in each group at the end of the 10th week; paraffin section of femur was stained with hematoxylin and eosin, 400×. <strong>(A)</strong> The control group femur. <strong>(B)</strong> The diabetic group femur. <strong>(C)</strong> The CS group femur. <strong>(D)</strong> The Met group femur. <strong>(E)</strong> The trabecular separation (Tb·Sp) in different groups. <strong>(F)</strong> The femoral thickness (Tb·Th) in different groups. <strong>(G)</strong> The percentage of bone trabecular area (BV/TV) in different groups; <sup>##</sup>indicates <i>p</i> < 0.01 compared with control. **indicates <i>p</i> < 0.01 compared with the diabetic group. BM. Bone marrow; Tb. Trabecular bone.</p></div><div class="DottedLine"></div><h3>Chondroitin Sulfate Inhibited Bone Marrow Lipogenesis of Type 1 Diabetic Rats</h3><p class="mb0">Compared with the control group, the number of bone marrow adipocytes of diabetic rats increased significantly, and the bone marrow adipocyte density and adipocyte diameter were larger than the control (<i>p</i> < 0.01) (<a href="#f7">Figure 7</a>). Ten weeks after CS or metformin treatment, the bone marrow adipocyte density and adipocyte diameter decreased (CS <i>vs</i>. T1DM, <i>p</i> < 0.01; Met <i>vs</i>. T1DM, <i>p</i> < 0.01) (<a href="#f7">Figure 7</a>). The results indicated that CS could inhibit bone marrow lipogenesis of type 1 diabetic rats.</p><div class="DottedLine"></div><div class="Imageheaders">FIGURE 7</div><div class="FigureDesc"><a href="https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g007.jpg" name="" target="_blank"> <picture> <source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=480&f=webp/https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g007.jpg" media="(max-width: 563px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=370&f=webp/https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g007.jpg" media="(max-width: 1024px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=290&f=webp/https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g007.jpg" media="(max-width: 1441px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=410&f=webp/https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g007.jpg" media=""><source type="image/jpg" srcset="https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g007.jpg" media=""> <img src="https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g007.jpg" alt="www.frontiersin.org" id="f7" loading="lazy"> </picture> </a><p><strong>Figure 7</strong> Adipocytes in the bone marrow cavity of the tibia in different groups at the end of the 10th week, H&E staining. <strong>(A)</strong> The control group tibia bone marrow. <strong>(B)</strong> The diabetic group tibia bone marrow. <strong>(C)</strong> The CS group tibia bone marrow. <strong>(D)</strong> The Met group tibia bone marrow. <strong>(E)</strong> Adipocyte density in different groups. <strong>(F)</strong> Adipocyte diameter in different groups. <sup>##</sup>indicates <i>p</i> < 0.01 compared with control. **indicates <i>p</i> < 0.01 compared with the diabetic group. Red arrows indicate adipocytes.</p></div><div class="DottedLine"></div><h3>Chondroitin Sulfate Inhibited Osteoclastogenesis of Type 1 Diabetic Rats</h3><p class="mb0">After TRAP staining, the osteoclasts were stained purplish red. There was an increased number of femoral osteoclasts in type 1 diabetic group rats compared with control (<i>p</i> < 0.01) (<a href="#f8">Figure 8</a>). Ten weeks after CS or metformin treatment, osteoclast number was decreased in the CS or Met group (CS group <i>vs</i>. T1DM group, <i>p</i> < 0.01; Met group <i>vs</i>. T1DM group, <i>p</i> < 0.01) (<a href="#f8">Figure 8E</a>), indicating that CS could inhibit osteoclasts proliferation in type 1 diabetic rats.</p><div class="DottedLine"></div><div class="Imageheaders">FIGURE 8</div><div class="FigureDesc"><a href="https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g008.jpg" name="" target="_blank"> <picture> <source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=480&f=webp/https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g008.jpg" media="(max-width: 563px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=370&f=webp/https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g008.jpg" media="(max-width: 1024px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=290&f=webp/https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g008.jpg" media="(max-width: 1441px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=410&f=webp/https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g008.jpg" media=""><source type="image/jpg" srcset="https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g008.jpg" media=""> <img src="https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g008.jpg" alt="www.frontiersin.org" id="f8" loading="lazy"> </picture> </a><p><strong>Figure 8</strong> The osteoclasts in femoral bone tissues of different groups at the end day of the 10th week. <strong>(A)</strong> The femoral bone tissues of control group rat. <strong>(B)</strong> The femoral bone tissues of diabetic group rat. <strong>(C)</strong> The femoral bone tissues of CS group rat. <strong>(D)</strong> The femoral bone tissues of Met group rat. <strong>(E)</strong> Number of osteoclasts per unit field in different groups. Bone tissues were stained by TRACP method, osteoclasts are multinucleate cells, and the red arrows point to osteoclasts. <sup>##</sup>indicates <i>p</i> < 0.01 compared with control. **indicates <i>p</i> < 0.01 compared with the diabetic group.</p></div><div class="DottedLine"></div><h3>Chondroitin Sulfate Upregulated OPG and RUNX 2 and Downregulated RANKL Expression in Bone Tissues</h3><p class="mb0">Pathological analysis showed that bone OPG and RUNX 2 expression levels were lowered in type 1 diabetic rats (T1DM <i>vs</i>. Control, <i>p</i> < 0.01); RANKL level in bone tissue was higher in type 1 diabetic rats (T1DM <i>vs</i>. Control, <i>p</i> < 0.01) (<a href="#f9">Figure 9</a>). After 10 weeks of CS or metformin administration, the bone OPG and RUNX 2 levels increased (CS or Met group <i>vs</i>. T1DM group, <i>p</i> < 0.01) and the RANKL level decreased (CS or Met <i>vs</i>. T1DM group, <i>p</i> < 0.01) (<a href="#f9">Figures 9A–C</a>).</p><div class="DottedLine"></div><div class="Imageheaders">FIGURE 9</div><div class="FigureDesc"><a href="https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g009.jpg" name="" target="_blank"> <picture> <source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=480&f=webp/https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g009.jpg" media="(max-width: 563px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=370&f=webp/https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g009.jpg" media="(max-width: 1024px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=290&f=webp/https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g009.jpg" media="(max-width: 1441px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=410&f=webp/https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g009.jpg" media=""><source type="image/jpg" srcset="https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g009.jpg" media=""> <img src="https://www.frontiersin.org/files/Articles/759843/fendo-12-759843-HTML/image_m/fendo-12-759843-g009.jpg" alt="www.frontiersin.org" id="f9" loading="lazy"> </picture> </a><p><strong>Figure 9</strong> Immunohistochemical staining of femur and positive staining percentage of OPG, RUNX2, and RANKL in each group. <strong>(A)</strong> The positive staining percentage of OPG in the femur of each group. <strong>(B)</strong> The positive staining percentage of RUNX 2 in the femur of each group. <strong>(C)</strong> The positive staining percentage of RANKL in the femur of each group. <sup>##</sup>indicates <i>p</i> < 0.01 compared with control. **indicates <i>p</i> < 0.01 compared with the diabetic group.</p></div><div class="DottedLine"></div><a id="h5" name="h5"></a><h2>Discussion</h2><p class="mb15">DOP is a serious metabolic bone disease associated with diabetes. It has the characteristics of reduced BMD, destruction of bone microstructure, increased brittleness, reduced strength, and easy to fracture, which seriously affects the quality of life of people with diabetes (<a href="#B18">18</a>, <a href="#B19">19</a>). Clinical treatment of DOP is to use chemical drugs such as vitamin D3, diphosphonate, calcitonin, and calcium to inhibit bone absorption, promote bone formation, and improve bone mineralization on the premise of controlling blood glucose. However, using chemical drugs long term can also lead to side effects, such as gastrointestinal diseases (<a href="#B20">20</a>). Therefore, natural anti-osteoporosis drugs are much popular.</p><p class="mb15">In the present study, we used the method of STZ injection to construct a rat model of type 1 diabetes, and intragastric administration of CS for 10 weeks. We detected the BMD, bone micro-CT, and bone pathology, and the results indicated that CS could inhibit bone loss, increase BMD, repair bone microstructure of type 1 diabetic rats, and thus prevent DOP.</p><p class="mb15">DOP is closely related to oxidative stress. Hyperglycemia induced reactive oxygen species (ROS) production <i>in vivo</i> and hindered the proliferation and differentiation of osteoblasts (<a href="#B21">21</a>–<a href="#B23">23</a>). It has been confirmed that a sharp increase in the level of ROS induces death of osteoblasts, resulting in bone structure damage and BMD reduction (<a href="#B24">24</a>). In the present study, we found that the SOD, GPX, and CAT activity levels were upregulated after 10 weeks of CS administration, indicating that CS could inhibit oxidative stress in type 1 diabetic rats; this may be one of important reasons why CS could prevent bone loss in type 1 diabetic rats.</p><p class="mb15">Inflammation is closely related to osteoporosis, which is another main cause of DOP (<a href="#B25">25</a>). The level of inflammatory cytokines in diabetes was significantly higher than that in healthy people, and accumulation of inflammatory cytokines could mediate oxidative stress damage, prompting osteoclast proliferation, increasing bone absorption, and thus causing osteoporosis (<a href="#B26">26</a>). In this study, we found that CS could inhibit the inflammation in type 1 diabetic rats, and inflammatory cytokines were downregulated by CS. Many other natural products have also been reported to relieve DOP through an anti-inflammatory manner (<a href="#B23">23</a>, <a href="#B27">27</a>–<a href="#B29">29</a>).</p><p class="mb15">Both osteoblasts and bone marrow adipocytes were derived from bone marrow mesenchymal stem cells (<a href="#B30">30</a>). As the number of bone marrow adipocytes increased, that of osteoblasts will decrease. Changes in the number and size of bone marrow adipocytes were positively correlated with osteoporosis, so they were important criteria for evaluating the efficacy of osteoporosis drugs (<a href="#B31">31</a>–<a href="#B33">33</a>). In diabetes, hyperglycemia promotes the differentiation of bone marrow adipocytes and inhibits osteoblast differentiation (<a href="#B34">34</a>). As indicated in the present study, the bone marrow adipocyte number and size in type 1 diabetic rats were higher than those in control group rats, which were downregulated by 10 weeks of CS administration. Our previous study also found that trace elements of zinc, black rice anthocyanin, and lycopene were all having a preventive effect on DOP, and all of them can inhibit bone marrow adipocyte generation (<a href="#B4">4</a>, <a href="#B23">23</a>, <a href="#B35">35</a>), which is consistent with the results of this study.</p><p class="mb15">Bone tissue structure is an important basis for evaluating bone health (<a href="#B36">36</a>). In this study, we applied bone micro-CT and bone tissue pathology techniques to evaluate bone structure; the results indicated that CS can improve bone structure lesions caused by diabetes, and it can effectively restore bone morphological parameters and upregulate BMD.</p><p class="mb15">The biochemical markers of bone turnover (BMBT) were metabolite of bone tissue. BMBT includes bone formation and bone resorption markers, which were important indicators for laboratory diagnosis of osteoporosis (<a href="#B37">37</a>, <a href="#B38">38</a>). Not only can it quickly reflect the process of bone formation and bone resorption, but it also can be used to reveal pathogenesis of metabolic bone disease, predict the rate of bone loss and fracture risk, and diagnose osteoporosis; at the same time, it can be used to quickly reflect the therapeutic effect of anti-osteoporosis drugs (<a href="#B39">39</a>). In our present study, the bone formation markers (osteocalcin and ALP) as well as bone resorption markers (TRACP 5b and CTX 1) all increased in type 1 diabetic rats, which indicated that diabetic rats had a higher bone turnover rate. This study showed that CS could downregulate the BMBT in diabetic rats and inhibit the higher bone turnover rate.</p><p class="mb15">RANKL was a member of the TNF superfamily involved in immune regulation and bone metabolism, and it was an important activator of osteoclast differentiation and maturation (<a href="#B40">40</a>). RANKL activates osteoclast differentiation, thus promoting bone resorption by competing with OPG to bind to receptor RANK. Overexpression of RANKL can lead to excessive activation of osteoclasts, which can lead to osteoporosis (<a href="#B41">41</a>). OPG was also a member of the TNF superfamily. It was highly expressed in testis and bone marrow (<a href="#B42">42</a>). OPG binds to RANKL and blocks binding of RANKL to RANK. At the same time, OPG can inhibit osteoclast differentiation and maturation, and promote osteoclasts apoptosis (<a href="#B43">43</a>). When the ratio of OPG to RANKL increases, bone formation activity of osteoblasts increases, and bone metabolism tends to be in a positive balance. When the ratio of OPG to RANKL decreases, the bone resorption activity of osteoclasts increases, and bone metabolism tends to be in a negative balance (<a href="#B44">44</a>). In the present study, the level of OPG/RANKL ratio in diabetic rats was greatly decreased compared with control, indicating increased bone resorption activity; after 10 weeks of CS treatment, the OPG/RANKL ratio was upregulated, indicating increased bone formation activity. One of the mechanisms of CS against DOP is by upregulating the OPG/RANKL ratio. In this study, we detected the bone OPG, RANKL, and RUNX 2 proteins using an immunohistochemical method, which has the advantage of localizing the protein, but in a quantitative aspect, it is inferior to Western blotting; in subsequent experiments, we will supplement the Western blotting experiment to confirm the above results.</p><p class="mb0">As a first-line drug for diabetes, metformin is a chemically synthesized drug. The main side effects are gastrointestinal reactions, such as nausea and vomiting (<a href="#B45">45</a>), as well as gut microbiota dysbiosis (<a href="#B46">46</a>). Secondly, metformin will interfere with the absorption of vitamin B12 and folic acid. Studies have shown that up to 30% of patients taking metformin have B12 deficiency (<a href="#B47">47</a>, <a href="#B48">48</a>). In this study, CS showed a good anti-DOP effect, similar to metformin. However, the CS used in this study was naturally extracted and has the advantages of high safety and less side effects compared with metformin. This study revealed the role of CS in DOP treatment through animal experiments. Later, we will further reveal its molecular mechanism through <i>in vitro</i> cell experiments and further confirm its effect through human experiments.</p><a id="h6" name="h6"></a><h2>Data Availability Statement</h2><p class="mb0">The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding authors.</p><a id="h7" name="h7"></a><h2>Ethics Statement</h2><p class="mb0">The animal study was reviewed and approved by Shaanxi University of Technology Animal Ethics Committee.</p><a id="h8" name="h8"></a><h2>Author Contributions</h2><p class="mb0">Study design: SQ, HZ, DC, TY, and XL. Study conduct: SQ, HZ, MS, ZS, YH, and SC. Data collection and analysis: SQ, HZ, MS, ZS, YH, and SC. Animal model construction: SQ and HZ. Histopathological experiment: SQ, MS, ZS, and SC. Manuscript draft: SQ. Manuscript revision: HZ. All authors contributed to the article and approved the submitted version.</p><a id="h9" name="h9"></a><h2>Funding</h2><p class="mb0">This research was funded by the Postdoctoral Program in Shaanxi University of Technology (SLGBH16-03), “Shaanxi Sanqin Scholar” Innovation Team, the Key Research Projects of Shaanxi Provincial Department of Education (20JY005), Shaanxi University of Technology Project (SLGKY2010), and the Key projects of Shaanxi Science and Technology Department (2021FP-14), and Shaanxi University of Technology Project (SLGKY2004).</p><a id="h10" name="h10"></a><h2>Conflict of Interest</h2><p class="mb0">The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p><a id="h11" name="h11"></a><h2>Publisher’s Note</h2><p class="mb15">All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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Endocrinol.</i> 12:759843. doi: 10.3389/fendo.2021.759843</p><p id="timestamps"><span>Received:</span> 17 August 2021; <span>Accepted:</span> 29 September 2021;<br><span>Published:</span> 27 October 2021.</p><div><p>Edited by:</p><a href="https://loop.frontiersin.org/people/42129">Peter Vestergaard</a>, Aalborg University Hospital, Denmark</div><div><p>Reviewed by:</p><a href="https://loop.frontiersin.org/people/742646">Ganesan Ramamoorthi</a>, Moffitt Cancer Center, United States<br><a href="https://loop.frontiersin.org/people/663338">Yaguang Li</a>, Central South University, China<br><a href="https://loop.frontiersin.org/people/1423801">Chen Chen</a>, Shaanxi University of Science and Technology, China</div><p><span>Copyright</span> © 2021 Qi, Shao, Sun, Chen, Hu, Li, Chen, Zheng and Yue. This is an open-access article distributed under the terms of the <a rel="license" href="http://creativecommons.org/licenses/by/4.0/" target="_blank">Creative Commons Attribution License (CC BY)</a>. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</p><p><span>*Correspondence:</span> Tian Li Yue, <a id="encmail">eXVldGxAbndhZnUuZWR1LmNu</a>; Hong Xing Zheng, <a id="encmail">emhlbmdob25neGluZ0BzbnV0LmVkdS5jbg==</a>; De Jing Chen, <a id="encmail">Y2Rqc2xnQDEyNi5jb20=</a></p><div class="clear"></div></div></div></div> <p class="AbstractSummary__disclaimer"><span>Disclaimer: </span> All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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src="https://loop.frontiersin.org/images/profile/42129/32" alt="Peter Vestergaard" class="Avatar__img is-inside-mask"></figure> <div class="ArticleDetailsEditors__ediorInfo__info"><div class="ArticleDetailsEditors__ediorInfo__name notranslate"> Peter Vestergaard </div> <div class="ArticleDetailsEditors__ediorInfo__affiliation notranslate"> Aalborg University Hospital, Denmark </div></div></a></div></div> <div class="ArticleDetailsEditors"><div class="ArticleDetailsEditors__editors"><div class="ArticleDetailsEditors__title">Reviewed by</div> <a href="https://loop.frontiersin.org/people/663338/overview" data-event="editorInfo-a-yaguangLi" class="ArticleDetailsEditors__ediorInfo"><figure class="Avatar Avatar--size-32"><img src="https://loop.frontiersin.org/images/profile/663338/32" alt="Yaguang Li" class="Avatar__img is-inside-mask"></figure> <div class="ArticleDetailsEditors__ediorInfo__info"><div class="ArticleDetailsEditors__ediorInfo__name notranslate"> Yaguang Li </div> <div class="ArticleDetailsEditors__ediorInfo__affiliation notranslate"> Second Xiangya Hospital, Central South University, China </div></div></a><a href="https://loop.frontiersin.org/people/742646/overview" data-event="editorInfo-a-ganesanRamamoorthi" class="ArticleDetailsEditors__ediorInfo"><figure class="Avatar Avatar--size-32"><img src="https://loop.frontiersin.org/images/profile/742646/32" alt="Ganesan Ramamoorthi" class="Avatar__img is-inside-mask"></figure> <div class="ArticleDetailsEditors__ediorInfo__info"><div class="ArticleDetailsEditors__ediorInfo__name notranslate"> Ganesan Ramamoorthi </div> <div class="ArticleDetailsEditors__ediorInfo__affiliation notranslate"> Moffitt Cancer Center, United States </div></div></a><a href="https://loop.frontiersin.org/people/1423801/overview" data-event="editorInfo-a-chenChen" class="ArticleDetailsEditors__ediorInfo"><figure class="Avatar Avatar--size-32"><img src="https://loop.frontiersin.org/images/profile/1423801/32" alt="Chen Chen" class="Avatar__img is-inside-mask"></figure> <div class="ArticleDetailsEditors__ediorInfo__info"><div class="ArticleDetailsEditors__ediorInfo__name notranslate"> Chen Chen </div> <div class="ArticleDetailsEditors__ediorInfo__affiliation notranslate"> Shaanxi University of Science and Technology, China </div></div></a></div></div> <div class="ArticleDetailsGlossary ArticleDetailsGlossary--open"><button class="ArticleDetailsGlossary__header"><div class="ArticleDetailsGlossary__header__title">Table of contents</div> <div class="ArticleDetailsGlossary__header__arrow"></div></button> <div class="ArticleDetailsGlossary__content"><ul class="flyoutJournal"><li><a href="#h1">Abstract</a></li><li><a href="#h2">Introduction</a></li><li><a href="#h3">Materials and Methods</a></li><li><a href="#h4">Results</a></li><li><a href="#h5">Discussion</a></li><li><a href="#h6">Data Availability Statement</a></li><li><a href="#h7">Ethics Statement</a></li><li><a href="#h8">Author Contributions</a></li><li><a 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It uncovers new therapies for prevalent health issues such as obesity, diabetes, reproduction, and aging.",mission:"\u003Cp\u003EFrontiers in Endocrinology is a journal that advances our understanding of the endocrine system and publishes research in novel therapies for prevalent health issues such as obesity, diabetes, disorders affecting the reproductive system, and the endocrinology of aging.\u003C\u002Fp\u003E \n\u003Cp\u003ELed by Field Chief Editor Jeff M. P. Holly (University of Bristol, UK), Frontiers in Endocrinology is indexed in MEDLINE, PubMed Central (PMC), Scopus and Web of Science (SCIE), among others, and welcomes research contributions in the various domains of endocrinology, bridging the gap between basic molecular structure and cellular communication, to clinical care. Topics include:\u003C\u002Fp\u003E\n\n\u003Cdiv\u003E • adrenal endocrinology\u003C\u002Fdiv\u003E\n\u003Cdiv\u003E • bone research\u003C\u002Fdiv\u003E\n\u003Cdiv\u003E • cancer endocrinology\u003C\u002Fdiv\u003E\n\u003Cdiv\u003E • cardiovascular endocrinology \u003C\u002Fdiv\u003E\n\u003Cdiv\u003E • cellular endocrinology \u003C\u002Fdiv\u003E\n\u003Cdiv\u003E • clinical diabetes\u003C\u002Fdiv\u003E\n\u003Cdiv\u003E • developmental endocrinology\u003C\u002Fdiv\u003E\n\u003Cdiv\u003E • diabetes: molecular mechanisms\u003C\u002Fdiv\u003E\n\u003Cdiv\u003E • endocrinology of aging\u003C\u002Fdiv\u003E\n\u003Cdiv\u003E • experimental endocrinology\u003C\u002Fdiv\u003E\n\u003Cdiv\u003E • gut endocrinology\u003C\u002Fdiv\u003E\n\u003Cdiv\u003E • molecular and structural endocrinology\u003C\u002Fdiv\u003E\n\u003Cdiv\u003E • neuroendocrine science\u003C\u002Fdiv\u003E\n\u003Cdiv\u003E • obesity\u003C\u002Fdiv\u003E\n\u003Cdiv\u003E • pediatric endocrinology \u003C\u002Fdiv\u003E\n\u003Cdiv\u003E • pituitary endocrinology\u003C\u002Fdiv\u003E\n\u003Cdiv\u003E • renal endocrinology\u003C\u002Fdiv\u003E\n\u003Cdiv\u003E • reproduction\u003C\u002Fdiv\u003E\n\u003Cdiv\u003E • systems endocrinology\u003C\u002Fdiv\u003E\n\u003Cdiv\u003E • thyroid endocrinology\u003C\u002Fdiv\u003E\n\u003Cdiv\u003E • translational and clinical endocrinology\u003C\u002Fdiv\u003E\n\u003Cbr\u003E\n  \n\u003Cp\u003EIn particular, the journal welcomes submissions which support and advance the UN’s Sustainable Development Goal (SDG), notably SDG 3: good health and well-being, in the effort to further our understanding as well as the prevention and treatment of hormonal disorders.\u003Cp\u003E\n\n\u003Cp\u003EManuscripts relating to diseases or disorders that do not relate to hormones are not suitable for publication in this journal. Manuscripts reporting bibliometric analyses will not be considered. In addition, manuscripts consisting solely of bioinformatics analysis of public in silico databases are not considered suitable unless supported by independent experimental verification.\u003Cp\u003E\n\n\u003Cp\u003EAuthors are still welcome to submit Systematic Reviews using publicly available data, but these must adhere to the PRISMA guidelines and include a completed \u003Ca href=\"http:\u002F\u002Fprisma-statement.org\u002Fdocuments\u002FPRISMA_2020_checklist.pdf\u002F\"\u003Echecklist\u003C\u002Fa\u003E with submission and have a conclusion related to endocrinology. Similarly meta-analyses must adhere to the PRISMA extension guidelines and include a completed \u003Ca href=\"http:\u002F\u002Fwww.prisma-statement.org\u002Fdocuments\u002FPRISMA%20NMA%20checklist.pdf\u002F\"\u003Echecklist\u003C\u002Fa\u003E with submission.\u003Cp\u003E\n\n\u003Cp\u003EFrontiers in Endocrinology is committed to advancing developments in the field of endocrinology by allowing unrestricted access to articles and communicating scientific knowledge to researchers and the public. This multidisciplinary open-access journal is at the forefront of disseminating impactful discoveries to researchers, academics, clinicians, and the public worldwide.\u003Cp\u003E\n\n",palette:"red",impactFactor:"5.2",citeScore:"5.6",citations:"188000",showTagline:f,twitter:"@FrontEndocrinol",__typename:"Journal"},currentFrontiersJournal:{id:x,name:t,slug:u,printISSN:f,shortName:L,electronicISSN:M,abbreviation:ac,specialtyId:f,publicationDate:f,isOnline:h,isOpenForSubmissions:h,spaceId:c,field:{id:ad,domainId:r,__typename:ae},__typename:a},articleHubSlug:e,articleHubPage:N,currentArticle:{id:759843,doi:af,title:ag,acceptanceDate:new Date(1632904830000),receptionDate:new Date(1629179177000),publicationDate:new Date(1635292800000),isPublished:h,abstract:ah,researchTopic:{id:23162,title:"Diabetes and Bone - From Cell to Human",articlesCount:O,isMagazinePage:m,slug:"diabetes-and-bone---from-cell-to-human",isOpenForSubmission:m},articleType:{id:24,name:"Original Research"},stage:{id:P,name:e},keywords:["chondroitin sulfate","diabetes","Osteoporosis","Bone microstructure","bone metabolism"],authors:[{id:ai,firstName:aj,lastName:"Qi",givenNames:aj,isCorresponding:m,isProfilePublic:h,userId:ai,affiliations:[{organizationName:ak,countryName:k,cityName:e,stateName:e,zipCode:e},{organizationName:q,countryName:k,cityName:e,stateName:e,zipCode:e},{organizationName:B,countryName:k,cityName:e,stateName:e,zipCode:e}]},{id:i,firstName:al,lastName:"Shao",givenNames:al,isCorresponding:h,isProfilePublic:m,userId:i,affiliations:[{organizationName:q,countryName:k,cityName:e,stateName:e,zipCode:e},{organizationName:B,countryName:k,cityName:e,stateName:e,zipCode:e}]},{id:i,firstName:am,lastName:"Sun",givenNames:am,isCorresponding:h,isProfilePublic:m,userId:i,affiliations:[{organizationName:q,countryName:k,cityName:e,stateName:e,zipCode:e},{organizationName:"QinLing-Bashan Mountains Bioresources Comprehensive Development C.I.C.",countryName:k,cityName:e,stateName:e,zipCode:e}]},{id:i,firstName:an,lastName:y,givenNames:an,isCorresponding:h,isProfilePublic:m,userId:i,affiliations:[{organizationName:q,countryName:k,cityName:e,stateName:e,zipCode:e}]},{id:i,firstName:ao,lastName:"Hu",givenNames:ao,isCorresponding:h,isProfilePublic:m,userId:i,affiliations:[{organizationName:q,countryName:k,cityName:e,stateName:e,zipCode:e}]},{id:i,firstName:ap,lastName:aq,givenNames:ap,isCorresponding:h,isProfilePublic:m,userId:i,affiliations:[{organizationName:q,countryName:k,cityName:e,stateName:e,zipCode:e},{organizationName:ar,countryName:k,cityName:e,stateName:e,zipCode:e}]},{id:i,firstName:as,lastName:y,givenNames:as,isCorresponding:h,isProfilePublic:m,userId:i,affiliations:[{organizationName:q,countryName:k,cityName:e,stateName:e,zipCode:e},{organizationName:B,countryName:k,cityName:e,stateName:e,zipCode:e}]},{id:at,firstName:au,lastName:"Zheng",givenNames:au,isCorresponding:h,isProfilePublic:h,userId:at,affiliations:[{organizationName:q,countryName:k,cityName:e,stateName:e,zipCode:e},{organizationName:B,countryName:k,cityName:e,stateName:e,zipCode:e},{organizationName:ar,countryName:k,cityName:e,stateName:e,zipCode:e}]},{id:i,firstName:av,lastName:"Yue",givenNames:av,isCorresponding:h,isProfilePublic:m,userId:i,affiliations:[{organizationName:ak,countryName:k,cityName:e,stateName:e,zipCode:e},{organizationName:"College of Food Science and Technology, Northwest University",countryName:k,cityName:e,stateName:e,zipCode:e}]}],editors:[{id:aw,firstName:ax,lastName:"Vestergaard",givenNames:ax,isCorresponding:m,isProfilePublic:h,userId:aw,affiliations:[{organizationName:"Aalborg University Hospital",countryName:"Denmark",cityName:e,stateName:e,zipCode:e}]}],reviewers:[{id:ay,firstName:az,lastName:aq,givenNames:az,isCorresponding:m,isProfilePublic:h,userId:ay,affiliations:[{organizationName:"Second Xiangya Hospital, Central South University",countryName:k,cityName:e,stateName:e,zipCode:e}]},{id:aA,firstName:aB,lastName:"Ramamoorthi",givenNames:aB,isCorresponding:m,isProfilePublic:h,userId:aA,affiliations:[{organizationName:"Moffitt Cancer Center",countryName:"United States",cityName:e,stateName:e,zipCode:e}]},{id:aC,firstName:y,lastName:y,givenNames:y,isCorresponding:m,isProfilePublic:h,userId:aC,affiliations:[{organizationName:"Shaanxi University of Science and Technology",countryName:k,cityName:e,stateName:e,zipCode:e}]}],journal:{id:x,slug:u,name:t,shortName:L,electronicISSN:M,field:{id:ad,domainId:r,__typename:ae},specialtyId:f,journalSectionPaths:[{section:aD,__typename:"journal_journalSectionPath"}],__typename:a},section:aD,impactMetrics:{views:7064,downloads:3722,citations:26},volume:Q,articleVolume:"Volume 12 - 2021",relatedArticles:[],isPublishedV2:m,contents:{titleHtml:"Chondroitin Sulfate Alleviates Diabetic Osteoporosis and Repairs Bone Microstructure \u003Ci\u003Evia\u003C\u002Fi\u003E Anti-Oxidation, Anti-Inflammation, and Regulating Bone Metabolism",fullTextHtml:"\u003Cdiv class=\"JournalAbstract\"\u003E\u003Ca id=\"h1\" name=\"h1\"\u003E\u003C\u002Fa\u003E\u003Cdiv class=\"authors\"\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\u003Ca href=\"https:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F889583\" class=\"user-id-889583\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fimages\u002Fprofile\u002F889583\u002F74\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\" alt=\"Shan Shan Qi,,\"\u003EShan Shan Qi\u003C\u002Fa\u003E\u003Csup\u003E1,2,3\u003C\u002Fsup\u003E\u003C\u002Fspan\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg\" alt=\"Meng Li Shao,\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\"\u003EMeng Li Shao\u003Csup\u003E2,3\u003C\u002Fsup\u003E\u003C\u002Fspan\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg\" alt=\"Ze Sun,\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\"\u003EZe Sun\u003Csup\u003E2,4\u003C\u002Fsup\u003E\u003C\u002Fspan\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg\" alt=\"Si Min Chen\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\"\u003ESi Min Chen\u003Csup\u003E2\u003C\u002Fsup\u003E\u003C\u002Fspan\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg\" alt=\"Ying Jun Hu\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\"\u003EYing Jun Hu\u003Csup\u003E2\u003C\u002Fsup\u003E\u003C\u002Fspan\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg\" alt=\"Xin Sheng Li,\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\"\u003EXin Sheng Li\u003Csup\u003E2,5\u003C\u002Fsup\u003E\u003C\u002Fspan\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg\" alt=\"De Jing Chen,*\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\"\u003EDe Jing Chen\u003Csup\u003E2,3*\u003C\u002Fsup\u003E\u003C\u002Fspan\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\u003Ca href=\"https:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F1397318\" class=\"user-id-1397318\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fimages\u002Fprofile\u002F1397318\u002F74\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\" alt=\"Hong Xing Zheng,,*\"\u003EHong Xing Zheng\u003C\u002Fa\u003E\u003Csup\u003E2,3,5*\u003C\u002Fsup\u003E\u003C\u002Fspan\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg\" alt=\"Tian Li Yue,*\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\"\u003ETian Li Yue\u003Csup\u003E1,6*\u003C\u002Fsup\u003E\u003C\u002Fspan\u003E\u003C\u002Fdiv\u003E\u003Cul class=\"notes\"\u003E\u003Cli\u003E\u003Cspan\u003E\u003Csup\u003E1\u003C\u002Fsup\u003E\u003C\u002Fspan\u003ECollege of Food Science and Engineering, Northwest Agriculture and Forestry (A&F) University, Yangling, China\u003C\u002Fli\u003E\u003Cli\u003E\u003Cspan\u003E\u003Csup\u003E2\u003C\u002Fsup\u003E\u003C\u002Fspan\u003ECollege of Biological Science and Engineering, Shaanxi University of Technology, Hanzhong, China\u003C\u002Fli\u003E\u003Cli\u003E\u003Cspan\u003E\u003Csup\u003E3\u003C\u002Fsup\u003E\u003C\u002Fspan\u003EQinba State Key Laboratory of Biological Resources and Ecological Environment, Hanzhong, China\u003C\u002Fli\u003E\u003Cli\u003E\u003Cspan\u003E\u003Csup\u003E4\u003C\u002Fsup\u003E\u003C\u002Fspan\u003EQinLing-Bashan Mountains Bioresources Comprehensive Development C.I.C., Hanzhong, China\u003C\u002Fli\u003E\u003Cli\u003E\u003Cspan\u003E\u003Csup\u003E5\u003C\u002Fsup\u003E\u003C\u002Fspan\u003EShaanxi Key Laboratory of Resource Biology, Hanzhong, China\u003C\u002Fli\u003E\u003Cli\u003E\u003Cspan\u003E\u003Csup\u003E6\u003C\u002Fsup\u003E\u003C\u002Fspan\u003ECollege of Food Science and Technology, Northwest University, Xi’an, China\u003C\u002Fli\u003E\u003C\u002Ful\u003E\u003Cp\u003EDiabetic osteoporosis (DOP) belongs to secondary osteoporosis caused by diabetes; it has the characteristics of high morbidity and high disability. In the present study, we constructed a type 1 diabetic rat model and administered chondroitin sulfate (200 mg\u002Fkg) for 10 weeks to observe the preventive effect of chondroitin sulfate on the bone loss of diabetic rats. The results showed that chondroitin sulfate can reduce blood glucose and relieve symptoms of diabetic rats; in addition, it can significantly increase the bone mineral density, improve bone microstructure, and reduce bone marrow adipocyte number in diabetic rats; after 10 weeks of chondroitin sulfate administration, the SOD activity level was upregulated, as well as CAT levels, indicating that chondroitin sulfate can alleviate oxidative stress in diabetic rats. Chondroitin sulfate was also found to reduce the level of serum inflammatory cytokines (TNF-α, IL-1, IL-6, and MCP-1) and alleviate the inflammation in diabetic rats; bone metabolism marker detection results showed that chondroitin sulfate can reduce bone turnover in diabetic rats (decreased RANKL, CTX-1, ALP, and TRACP 5b levels were observed after 10 weeks of chondroitin sulfate administration). At the same time, the bone OPG and RUNX 2 expression levels were higher after chondroitin sulfate treatment, the bone RANKL expression was lowered, and the OPG\u002FRANKL ratio was upregulated. All of the above indicated that chondroitin sulfate could prevent STZ-induced DOP and repair bone microstructure; the main mechanism was through anti-oxidation, anti-inflammatory, and regulating bone metabolism. Chondroitin sulfate could be used to develop anti-DOP functional foods and diet interventions for diabetes.\u003C\u002Fp\u003E\u003Cdiv class=\"clear\"\u003E\u003C\u002Fdiv\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"JournalFullText\"\u003E\u003Ca id=\"h2\" name=\"h2\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EIntroduction\u003C\u002Fh2\u003E\u003Cp class=\"mb15\"\u003EThere are 463 million people with diabetes worldwide currently, an average of 1 in 11 adults (20–79 years old), and by 2045, the diabetes population will jump to 700 million (\u003Ca href=\"#B1\"\u003E1\u003C\u002Fa\u003E, \u003Ca href=\"#B2\"\u003E2\u003C\u002Fa\u003E). Long-term high blood glucose can cause microvascular injury, endangering the kidneys, heart, eyes, peripheral nerves, brain, feet, as well as bone (\u003Ca href=\"#B3\"\u003E3\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\u003Cp class=\"mb15\"\u003EDiabetic osteoporosis (DOP) is a bone complication caused by diabetes, characterized by lowered bone mineral density (BMD), changes of bone microstructure, and raised bone fragility. DOP greatly reduces the quality of living of patients, subjecting them to heavy economic burden (\u003Ca href=\"#B4\"\u003E4\u003C\u002Fa\u003E). As the number of people with diabetes increases globally, the number of DOP is also increasing annually. Clinical data showed that about 50% to 65% of people with diabetes have decreased BMD and increased incidence of fractures, and nearly 35% of them have been diagnosed as osteoporosis (\u003Ca href=\"#B5\"\u003E5\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\u003Cp class=\"mb15\"\u003EThe present approaches for DOP are oral hypoglycemic drugs or insulin injections, supplemented by calcium preparations, bisphosphonates, etc. (\u003Ca href=\"#B6\"\u003E6\u003C\u002Fa\u003E). However, adverse drug reactions have always been a major challenge related to drug treatment goals. Therefore, exploring more safer and effective strategies are highly crucial.\u003C\u002Fp\u003E\u003Cp class=\"mb0\"\u003EChondroitin sulfate (CS) is a natural sticky polysaccharide made from the cartilage of animals. The content of CS is different in the cartilage of different species and ages. As a drug for the treatment of joint diseases, it was used in conjunction with glucosamine to relieve pain and promote cartilage regeneration, which can fundamentally improve joint problems (\u003Ca href=\"#B7\"\u003E7\u003C\u002Fa\u003E). It was reported that CS has anti-inflammation effects (\u003Ca href=\"#B8\"\u003E8\u003C\u002Fa\u003E), has anti-psoriasis effects (\u003Ca href=\"#B9\"\u003E9\u003C\u002Fa\u003E), enhances immunity (\u003Ca href=\"#B10\"\u003E10\u003C\u002Fa\u003E), lowers blood lipid (\u003Ca href=\"#B11\"\u003E11\u003C\u002Fa\u003E), and has anti-tumor effects (\u003Ca href=\"#B12\"\u003E12\u003C\u002Fa\u003E). It also has a preventive effect on diabetic nephropathy.in streptozotocin (STZ)-induced diabetic mice (\u003Ca href=\"#B13\"\u003E13\u003C\u002Fa\u003E), and CS was also reported to increase bone formation in ovariectomized rats (\u003Ca href=\"#B14\"\u003E14\u003C\u002Fa\u003E). Whether it has a protective effect on DOP has not been studied. Our previous study found that the CS could increase the BMD of diabetic rats, but the mechanisms were not clear. So, in present study, we researched the protective effect and mechanisms of CS on DOP, which will provide a new approach for DOP treatment.\u003C\u002Fp\u003E\u003Ca id=\"h3\" name=\"h3\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EMaterials and Methods\u003C\u002Fh2\u003E\u003Ch3\u003EChemicals\u003C\u002Fh3\u003E\u003Cp class=\"mb0\"\u003ECS power was isolated and purified from the cartilage of giant salamander according to the method of Zhu (\u003Ca href=\"#B15\"\u003E15\u003C\u002Fa\u003E); the content of CS in the experimental materials was 95%. STZ was obtained from Acmec Biochemical Company (Shanghai, China).\u003C\u002Fp\u003E\u003Ch3\u003EAnimals\u003C\u002Fh3\u003E\u003Cp class=\"mb0\"\u003EFifty-six-day old male rats were obtained from Cheng Du Dashuo Experimental Animal Company (Cheng Du, China, license no. SCXK 2020-030). Animals were kept in independent ventilated cages in a standardized animal room with constant temperature and humidity. Water and food intake of animals was not restricted. Animals were feed with diets prepared by the American Society of Nutrition (AIN93) standard. Animal experiment operations were approved by Shaanxi University of Technology Animal Ethics Committee (approval No. 2020-74).\u003C\u002Fp\u003E\u003Ch3\u003EDiabetes Induction in SD Rats, Animal Grouping, and Treatment\u003C\u002Fh3\u003E\u003Cp class=\"mb15\"\u003EAfter 7 days of acclimatization, except for 10 animals in the control group, the remaining animals were intraperitoneally injected with 45 mg\u002Fkg of STZ after fasting overnight, and the dosage of STZ was based on our previous study (\u003Ca href=\"#B16\"\u003E16\u003C\u002Fa\u003E, \u003Ca href=\"#B17\"\u003E17\u003C\u002Fa\u003E); STZ was dissolved in citric acid buffer solution at pH 4.3, and 10 animals in the control group were injected with citric acid buffer solution. After 72 h, animal’s blood glucose was detected, and animals with blood glucose higher than 11.1 mmol\u002FL were selected for subsequent experiments.\u003C\u002Fp\u003E\u003Cp class=\"mb15\"\u003EThen, animals were regrouped into four groups: Group 1, control group (\u003Ci\u003En\u003C\u002Fi\u003E = 10), rats were given deionized water by gavage every day; Group 2, type 1 diabetic group (\u003Ci\u003En\u003C\u002Fi\u003E = 10), named T1DM group, type 1 diabetic rats were given deionized water by gavage every day; Group 3, CS-treated group (\u003Ci\u003En\u003C\u002Fi\u003E = 10), named CS group, type 1 diabetic rats were given CS (200 mg\u002Fkg\u002Fday) by gavage every day; Group 4, metformin group (\u003Ci\u003En\u003C\u002Fi\u003E = 10), named Met group, type 1 diabetic rats were given metformin (200 mg\u002Fkg\u002Fday) by gavage every day. The dose of CS was selected by pre-experiment.\u003C\u002Fp\u003E\u003Cp class=\"mb0\"\u003EDuring the experiment, animals were weighed every week, water and diet of animals were recorded, and the blood glucose of animals was measured every week. After 10 weeks of administration, animals were anesthetized with isoflurane and were sacrificed by cervical dislocation; blood was collected, and serum was separated and stored at −80°C. At the same time, femurs, vertebrae, and tibias of animals were collected.\u003C\u002Fp\u003E\u003Ch3\u003EBMD Measurement\u003C\u002Fh3\u003E\u003Cp class=\"mb0\"\u003EThe BMD of femur and vertebrae of each rat were obtained by using small-animal dual-energy X-ray absorptiometry (InAlzyer, Korea).\u003C\u002Fp\u003E\u003Ch3\u003EBone Micro-CT Measurement\u003C\u002Fh3\u003E\u003Cp class=\"mb0\"\u003EFemur tissues of rats were collected and scanned by a Locus SP micro-CT (GE Healthcare, Danderyd, Sweden) with a resolution of 6.5μm. The processing and analysis software were MICVIEW 3D reconstruction processing software and ABA-specific bone analysis software. The data of cortex volume, bone surface area, trabecular number, and bone volume were obtained by using ABA-specific bone analysis software.\u003C\u002Fp\u003E\u003Ch3\u003EBone Turnover Marker Detection\u003C\u002Fh3\u003E\u003Cp class=\"mb0\"\u003EAccording to instructions listed in ELISA test kits (Elabscience, Wuhan, China), a microplate reader (Elx808, Winooski, USA) was used to detect the content of bone turnover markers (CTX-1, OPG, ALP, TRACP 5b, RANKL, osteocalcin, and RUNX 2) in serum of each group of rats.\u003C\u002Fp\u003E\u003Ch3\u003EOxidative Stress Index Detection\u003C\u002Fh3\u003E\u003Cp class=\"mb0\"\u003EAccording to instructions listed in kits (Beyotime, Shanghai, China), SOD activity, MDA content, CAT activity, and GSH content in serum were detected by an ultraviolet and visible spectrophotometer (Alpha1860S, Shanghai, China).\u003C\u002Fp\u003E\u003Ch3\u003EInflammatory Cytokine Detection\u003C\u002Fh3\u003E\u003Cp class=\"mb0\"\u003EBased on instructions listed in ELISA test kits (Elabscience, Wuhan, China), the microplate reader (Elx808, Winooski, USA) was used to detect the content of serum inflammatory cytokines (IL-6, TNF-α, MCP-1, and IL-1).\u003C\u002Fp\u003E\u003Ch3\u003EPathological Analysis of Femur Bone Tissue\u003C\u002Fh3\u003E\u003Cp class=\"mb0\"\u003EFemur of each rat was fixed in 3.8% paraformaldehyde solution for 48 h, then rinsed with PBS, placed in 10% EDTA solution for 5 weeks, and then made into 4-micron-thick paraffin sections by a tissue slicer (Leica, Wetzlar, Germany), and the sections were stained with hematoxylin and eosin, sealed with neutral gum. After that, a slide was placed under a microscope to observe femur pathological changes. Bone morphometric parameters including trabecular separation (Tb·Sp), bone volume per tissue volume (BV\u002FTV), and trabecular thickness (Tb·Th) were analyzed by image pro plus (IPP) 6.0 software.\u003C\u002Fp\u003E\u003Ch3\u003EPathological Observation of Tibia Bone Marrow Adipocytes\u003C\u002Fh3\u003E\u003Cp class=\"mb0\"\u003ETibia of each rat was fixed in 3.8% paraformaldehyde solution for 48 h, then rinsed with PBS; femur was placed in 10% EDTA solution for 5 weeks and then made into 4-micron-thick paraffin sections by a tissue slicer (Leica, Wetzlar, Germany), and sections were stained with hematoxylin and eosin, sealed with neutral gum. After that, the slide was placed under a microscope to observe bone marrow adipocytes in tibia. Adipocytes were counted in each field, and the diameter of adipocytes was measured with IPP 6.0 software.\u003C\u002Fp\u003E\u003Ch3\u003EFemur Osteoclast Observation-TRAP Staining\u003C\u002Fh3\u003E\u003Cp class=\"mb0\"\u003EFour-micron-thick femur paraffin sections were stained with TRAP staining kit, based on the instructions listed in the kit. The stained slides were sealed with neutral gum. After that, a slide was placed under a microscope (200× magnification) to observe osteoclasts in the femur. Osteoclasts were purple-red after staining, five fields of view were selected for each slice, and the number of osteoclasts in each field was counted.\u003C\u002Fp\u003E\u003Ch3\u003EImmunohistochemical\u003C\u002Fh3\u003E\u003Cp class=\"mb0\"\u003EFemur paraffin slides (4 μm thick) were soaked in xylene for 20 min, and then slides were dehydrated with gradient ethanol and placed in a water bath at 95°C in citrate antigen retrieval solution (pH 6) for 1 h. After cooling to room temperature, slides were washed with PBS; 1% BSA solution was added to the slides to block endogenous peroxidase, and then the slides were washed with PBS, incubated with primary antibodies (OPG, RANKL, and RUNX2, respectively) (Santa Cruz Biotech, USA) for 1.5 h at 37°C in a constant temperature incubator, double washed with PBS, incubated with secondary antibody (Santa Cruz Biotech, USA) for 2 h, washed with PBS three times, and then incubated with DAB. After that, slides were counterstained with hematoxylin, and sealed with neutral gum. IHC-stained slides were observed under a microscope (Olympus, Germany) with 200× magnification. Five fields of view were chosen for each slice, and IPP software was used to count the area of positive staining, and percentage of positive area was calculated.\u003C\u002Fp\u003E\u003Ch3\u003EStatistical Analysis\u003C\u002Fh3\u003E\u003Cp class=\"mb0\"\u003EStatistical analyses were performed with ANOVA by SPASS 19.0; all of the data were shown as mean ± SD, and statistical significance was compared between groups using the LSD method. \u003Ci\u003Ep\u003C\u002Fi\u003E < 0.05 was considered significant, and \u003Ci\u003Ep\u003C\u002Fi\u003E < 0.01 was considered extremely significant.\u003C\u002Fp\u003E\u003Ca id=\"h4\" name=\"h4\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EResults\u003C\u002Fh2\u003E\u003Ch3\u003EChondroitin Sulfate Relieved the Symptoms of Hyperglycemia, Polydipsia, and Polyphagia Caused by Diabetes in SD Rats\u003C\u002Fh3\u003E\u003Cp class=\"mb0\"\u003EThe blood glucose, water intake, and food intake in type 1 diabetic rats were significantly increased compared with control (\u003Ci\u003Ep\u003C\u002Fi\u003E < 0.01) (\u003Ca href=\"#f1\"\u003EFigures 1A, C, D\u003C\u002Fa\u003E), while the body weight was decreased (\u003Ca href=\"#f1\"\u003EFigure 1B\u003C\u002Fa\u003E); this result was consistent with basic pathological changes of diabetes, indicating that the type 1 diabetes animal model was successfully established. After 10 weeks of CS or metformin administration, the symptoms of diabetes in rats were effectively alleviated, reflected in lowered blood glucose, increased body weight, and reduced water and food intake. This indicates that CS can reduce blood glucose of diabetic rats and relieve the symptoms of diabetes.\u003C\u002Fp\u003E\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"Imageheaders\"\u003EFIGURE 1\u003C\u002Fdiv\u003E\u003Cdiv class=\"FigureDesc\"\u003E\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g001.jpg\" name=\"\" target=\"_blank\"\u003E\n \u003Cpicture\u003E\n \u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=480&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g001.jpg\" media=\"(max-width: 563px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=370&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g001.jpg\" media=\"(max-width: 1024px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=290&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g001.jpg\" media=\"(max-width: 1441px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=410&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g001.jpg\" media=\"\"\u003E\u003Csource type=\"image\u002Fjpg\" srcset=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g001.jpg\" media=\"\"\u003E \u003Cimg src=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g001.jpg\" alt=\"www.frontiersin.org\" id=\"f1\" loading=\"lazy\"\u003E\n \u003C\u002Fpicture\u003E\n\u003C\u002Fa\u003E\u003Cp\u003E\u003Cstrong\u003EFigure 1\u003C\u002Fstrong\u003E Blood glucose, body weight, food intake, and water intake at the end of the 10th week in different groups. \u003Cstrong\u003E(A)\u003C\u002Fstrong\u003E Blood glucose in different groups. \u003Cstrong\u003E(B)\u003C\u002Fstrong\u003E Body weight in different groups. \u003Cstrong\u003E(C)\u003C\u002Fstrong\u003E Food intake in different groups. \u003Cstrong\u003E(D)\u003C\u002Fstrong\u003E Water intake in different groups. \u003Csup\u003E##\u003C\u002Fsup\u003Eindicates \u003Ci\u003Ep\u003C\u002Fi\u003E < 0.01 compared with control; **indicates \u003Ci\u003Ep\u003C\u002Fi\u003E < 0.01 compared with the diabetic group; *indicates \u003Ci\u003Ep\u003C\u002Fi\u003E < 0.05 compared with the diabetic group.\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\u003Ch3\u003EChondroitin Sulfate Increased BMD of Type 1 Diabetic Rats\u003C\u002Fh3\u003E\u003Cp class=\"mb0\"\u003ECompared with control group, the BMD (lumbar vertebrae and femur) in diabetic rats was lowered significantly (\u003Ci\u003Ep\u003C\u002Fi\u003E < 0.01) (\u003Ca href=\"#f2\"\u003EFigure 2\u003C\u002Fa\u003E). After 10 weeks of CS or metformin administration, the BMD in lumbar vertebrae and femur was increased (CS \u003Ci\u003Evs\u003C\u002Fi\u003E. T1DM group, \u003Ci\u003Ep\u003C\u002Fi\u003E < 0.01; Metformin \u003Ci\u003Evs\u003C\u002Fi\u003E. T1DM groups, \u003Ci\u003Ep\u003C\u002Fi\u003E < 0.01) (\u003Ca href=\"#f2\"\u003EFigure 2\u003C\u002Fa\u003E), indicating that CS could increase the BMD of type 1 diabetic rats.\u003C\u002Fp\u003E\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"Imageheaders\"\u003EFIGURE 2\u003C\u002Fdiv\u003E\u003Cdiv class=\"FigureDesc\"\u003E\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g002.jpg\" name=\"\" target=\"_blank\"\u003E\n \u003Cpicture\u003E\n \u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=480&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g002.jpg\" media=\"(max-width: 563px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=370&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g002.jpg\" media=\"(max-width: 1024px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=290&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g002.jpg\" media=\"(max-width: 1441px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=410&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g002.jpg\" media=\"\"\u003E\u003Csource type=\"image\u002Fjpg\" srcset=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g002.jpg\" media=\"\"\u003E \u003Cimg src=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g002.jpg\" alt=\"www.frontiersin.org\" id=\"f2\" loading=\"lazy\"\u003E\n \u003C\u002Fpicture\u003E\n\u003C\u002Fa\u003E\u003Cp\u003E\u003Cstrong\u003EFigure 2\u003C\u002Fstrong\u003E The bone mineral density of different groups at the end of the 10th week. \u003Cstrong\u003E(A)\u003C\u002Fstrong\u003E The BMD of lumbar vertebrae in different groups. \u003Cstrong\u003E(B)\u003C\u002Fstrong\u003E The femoral BMD in different groups. \u003Csup\u003E##\u003C\u002Fsup\u003Eindicates \u003Ci\u003Ep\u003C\u002Fi\u003E < 0.01 compared with control. **indicates \u003Ci\u003Ep\u003C\u002Fi\u003E < 0.01 compared with the diabetic group.\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\u003Ch3\u003EChondroitin Sulfate Repaired Bone Micro-CT Structure of Type 1 Diabetic Rats\u003C\u002Fh3\u003E\u003Cp class=\"mb0\"\u003EFemur micro-CT scanning results showed that trabecular structure in the model group was sparse, and some trabecular areas disappeared (\u003Ca href=\"#f3\"\u003EFigure 3A\u003C\u002Fa\u003E). After 10 weeks of administration of CS or metformin, trabecular structure was repaired. Micro-CT metrological data (\u003Ca href=\"#f3\"\u003EFigures 3A–E\u003C\u002Fa\u003E) showed that cortical bone volume, bone surface area, number of bone trabecular, and bone volume in type 1 diabetic group were significantly lower than those in the control group (\u003Ci\u003Ep\u003C\u002Fi\u003E < 0.01). After 10 weeks of CS or metformin administration, the above indexes were upregulated, and the differences were significant compared with the diabetic group.\u003C\u002Fp\u003E\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"Imageheaders\"\u003EFIGURE 3\u003C\u002Fdiv\u003E\u003Cdiv class=\"FigureDesc\"\u003E\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g003.jpg\" name=\"\" target=\"_blank\"\u003E\n \u003Cpicture\u003E\n \u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=480&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g003.jpg\" media=\"(max-width: 563px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=370&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g003.jpg\" media=\"(max-width: 1024px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=290&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g003.jpg\" media=\"(max-width: 1441px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=410&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g003.jpg\" media=\"\"\u003E\u003Csource type=\"image\u002Fjpg\" srcset=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g003.jpg\" media=\"\"\u003E \u003Cimg src=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g003.jpg\" alt=\"www.frontiersin.org\" id=\"f3\" loading=\"lazy\"\u003E\n \u003C\u002Fpicture\u003E\n\u003C\u002Fa\u003E\u003Cp\u003E\u003Cstrong\u003EFigure 3\u003C\u002Fstrong\u003E \u003Cstrong\u003E(A)\u003C\u002Fstrong\u003E The femur micro-CT structure of different groups at the end of the 10th week. \u003Cstrong\u003E(B)\u003C\u002Fstrong\u003E Cortex volume in different groups. \u003Cstrong\u003E(C)\u003C\u002Fstrong\u003E Bone surface area in different groups. \u003Cstrong\u003E(D)\u003C\u002Fstrong\u003E Trabecular number in different groups. \u003Cstrong\u003E(E)\u003C\u002Fstrong\u003E Bone volume in different groups. \u003Csup\u003E##\u003C\u002Fsup\u003Eindicates \u003Ci\u003Ep\u003C\u002Fi\u003E < 0.01 compared with control. **indicates \u003Ci\u003Ep\u003C\u002Fi\u003E < 0.01 compared with the diabetic group.\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\u003Ch3\u003EChondroitin Sulfate Regulated Bone Turnover of Type 1 Diabetic Rats\u003C\u002Fh3\u003E\u003Cp class=\"mb0\"\u003EAs \u003Ca href=\"#T1\"\u003ETable 1\u003C\u002Fa\u003E shows, some of the serum bone turnover markers (OPG, RUNX 2, osteocalcin, and TRACP 5b) and OPG\u002FRANKL ratio levels were lowered in type 1 diabetic rats compared with control (\u003Ci\u003Ep\u003C\u002Fi\u003E < 0.01), and those were significantly increased in the CS and Met group compared with the type 1 diabetic group. Other serum bone turnover markers such as RANKL, CTX 1, and ALP levels were higher in the type 1 diabetic group compared with the control (\u003Ci\u003Ep\u003C\u002Fi\u003E < 0.01), which were significantly decreased in CS and Met groups, indicating that CS could regulate bone turnover of type 1 diabetic rats.\u003C\u002Fp\u003E\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"Imageheaders\"\u003ETABLE 1\u003C\u002Fdiv\u003E\u003Cdiv class=\"FigureDesc\"\u003E\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-t001.jpg\" name=\"table 1\" target=\"_blank\"\u003E\n \u003Cpicture\u003E\n \u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=480&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-t001.jpg\" media=\"(max-width: 563px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=370&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-t001.jpg\" media=\"(max-width: 1024px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=290&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-t001.jpg\" media=\"(max-width: 1441px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=410&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-t001.jpg\" media=\"\"\u003E\u003Csource type=\"image\u002Fjpg\" srcset=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-t001.jpg\" media=\"\"\u003E \u003Cimg src=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-t001.jpg\" alt=\"www.frontiersin.org\" id=\"T1\" loading=\"lazy\"\u003E\n \u003C\u002Fpicture\u003E\n\u003C\u002Fa\u003E\u003Cp\u003E\u003Cstrong\u003ETable 1\u003C\u002Fstrong\u003E Bone turnover markers in different groups at the end of the 10th week.\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\u003Ch3\u003EChondroitin Sulfate Downregulated Inflammatory Cytokines of Type 1 Diabetic Rats\u003C\u002Fh3\u003E\u003Cp class=\"mb0\"\u003ESerum inflammatory cytokine levels in type 1 diabetic rats increased dramatically compared with the control group (\u003Ci\u003Ep\u003C\u002Fi\u003E < 0.01). After 10 weeks of CS or metformin treatment, the serum inflammatory cytokine levels were lowered in CS or Met groups (CS \u003Ci\u003Evs\u003C\u002Fi\u003E. T1DM group, \u003Ci\u003Ep\u003C\u002Fi\u003E < 0.01; Metformin \u003Ci\u003Evs\u003C\u002Fi\u003E. T1DM groups, \u003Ci\u003Ep\u003C\u002Fi\u003E < 0.01) (\u003Ca href=\"#f4\"\u003EFigure 4\u003C\u002Fa\u003E), indicating that CS has an inhibitory effect on inflammation induced by type 1 diabetes in SD rats.\u003C\u002Fp\u003E\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"Imageheaders\"\u003EFIGURE 4\u003C\u002Fdiv\u003E\u003Cdiv class=\"FigureDesc\"\u003E\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g004.jpg\" name=\"\" target=\"_blank\"\u003E\n \u003Cpicture\u003E\n \u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=480&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g004.jpg\" media=\"(max-width: 563px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=370&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g004.jpg\" media=\"(max-width: 1024px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=290&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g004.jpg\" media=\"(max-width: 1441px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=410&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g004.jpg\" media=\"\"\u003E\u003Csource type=\"image\u002Fjpg\" srcset=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g004.jpg\" media=\"\"\u003E \u003Cimg src=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g004.jpg\" alt=\"www.frontiersin.org\" id=\"f4\" loading=\"lazy\"\u003E\n \u003C\u002Fpicture\u003E\n\u003C\u002Fa\u003E\u003Cp\u003E\u003Cstrong\u003EFigure 4\u003C\u002Fstrong\u003E The serum inflammatory cytokine levels in different groups at the end of the 10th week. \u003Cstrong\u003E(A)\u003C\u002Fstrong\u003E MCP-1 levels in serum; \u003Cstrong\u003E(B)\u003C\u002Fstrong\u003E IL-6 levels in serum; \u003Cstrong\u003E(C)\u003C\u002Fstrong\u003E IL-1 levels in serum; \u003Cstrong\u003E(D)\u003C\u002Fstrong\u003E TNF-a levels in serum. \u003Csup\u003E##\u003C\u002Fsup\u003Eindicates \u003Ci\u003Ep\u003C\u002Fi\u003E < 0.01 compared with control. **indicates \u003Ci\u003Ep\u003C\u002Fi\u003E < 0.01 compared with the diabetic group.\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\u003Ch3\u003EChondroitin Sulfate Alleviated Oxidative Stress in Type 1 Diabetic Rats\u003C\u002Fh3\u003E\u003Cp class=\"mb0\"\u003EOxidative stress existed in diabetic rats; serum SOD, GPX, and CAT activity levels were lowered, and MDA level was raised in type 1 diabetic rats. Ten weeks after CS or metformin treatment, SOD, GPX, and CAT activity levels were raised, and MDA level was lowered (CS \u003Ci\u003Evs\u003C\u002Fi\u003E. T1DM, \u003Ci\u003Ep\u003C\u002Fi\u003E < 0.01; Met \u003Ci\u003Evs\u003C\u002Fi\u003E. T1DM, \u003Ci\u003Ep\u003C\u002Fi\u003E < 0.01) (\u003Ca href=\"#f5\"\u003EFigure 5\u003C\u002Fa\u003E). The results indicated that CS could alleviate oxidative stress in T1DM rats.\u003C\u002Fp\u003E\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"Imageheaders\"\u003EFIGURE 5\u003C\u002Fdiv\u003E\u003Cdiv class=\"FigureDesc\"\u003E\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g005.jpg\" name=\"\" target=\"_blank\"\u003E\n \u003Cpicture\u003E\n \u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=480&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g005.jpg\" media=\"(max-width: 563px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=370&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g005.jpg\" media=\"(max-width: 1024px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=290&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g005.jpg\" media=\"(max-width: 1441px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=410&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g005.jpg\" media=\"\"\u003E\u003Csource type=\"image\u002Fjpg\" srcset=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g005.jpg\" media=\"\"\u003E \u003Cimg src=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g005.jpg\" alt=\"www.frontiersin.org\" id=\"f5\" loading=\"lazy\"\u003E\n \u003C\u002Fpicture\u003E\n\u003C\u002Fa\u003E\u003Cp\u003E\u003Cstrong\u003EFigure 5\u003C\u002Fstrong\u003E The level of serum oxidative stress parameters in different groups at the end of the 10th week. \u003Cstrong\u003E(A)\u003C\u002Fstrong\u003E The level of SOD activities in different groups. \u003Cstrong\u003E(B)\u003C\u002Fstrong\u003E The level of glutathione peroxidase (GPX) activities in different groups. \u003Cstrong\u003E(C)\u003C\u002Fstrong\u003E The level of catalase (CAT) activities in different groups. \u003Cstrong\u003E(D)\u003C\u002Fstrong\u003E The level of malondialdehyde (MDA) content in different groups; \u003Csup\u003E##\u003C\u002Fsup\u003Eindicates \u003Ci\u003Ep\u003C\u002Fi\u003E < 0.01 compared with control, **indicates \u003Ci\u003Ep\u003C\u002Fi\u003E < 0.01 compared with the diabetic group.\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\u003Ch3\u003EChondroitin Sulfate Repaired Bone Microstructure of Type 1 Diabetic Rats\u003C\u002Fh3\u003E\u003Cp class=\"mb0\"\u003ECompared with the control group, the femoral bone of diabetic rats was sparse and fractured, the spacing of trabecular bone became wider, and the trabecular bone became thinner (\u003Ca href=\"#f6\"\u003EFigures 6A–D\u003C\u002Fa\u003E). The femoral structure was repaired after 10 weeks of CS or metformin administration. The results of bone morphometric data (\u003Ca href=\"#f6\"\u003EFigures 6E–G\u003C\u002Fa\u003E) showed that the femoral thickness (Tb·Th) and the percentage of bone trabecular area (BV\u002FTV) in CS or metformin treatment groups were significantly increased compared with the type 1 diabetic group (\u003Ci\u003Ep\u003C\u002Fi\u003E < 0.01), and the trabecular separation (Tb·Sp) was decreased in CS or metformin treatment groups compared with the type 1 diabetic group (\u003Ci\u003Ep\u003C\u002Fi\u003E < 0.01).\u003C\u002Fp\u003E\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"Imageheaders\"\u003EFIGURE 6\u003C\u002Fdiv\u003E\u003Cdiv class=\"FigureDesc\"\u003E\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g006.jpg\" name=\"\" target=\"_blank\"\u003E\n \u003Cpicture\u003E\n \u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=480&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g006.jpg\" media=\"(max-width: 563px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=370&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g006.jpg\" media=\"(max-width: 1024px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=290&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g006.jpg\" media=\"(max-width: 1441px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=410&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g006.jpg\" media=\"\"\u003E\u003Csource type=\"image\u002Fjpg\" srcset=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g006.jpg\" media=\"\"\u003E \u003Cimg src=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g006.jpg\" alt=\"www.frontiersin.org\" id=\"f6\" loading=\"lazy\"\u003E\n \u003C\u002Fpicture\u003E\n\u003C\u002Fa\u003E\u003Cp\u003E\u003Cstrong\u003EFigure 6\u003C\u002Fstrong\u003E The pathological sections of femur of rats in each group at the end of the 10th week; paraffin section of femur was stained with hematoxylin and eosin, 400×. \u003Cstrong\u003E(A)\u003C\u002Fstrong\u003E The control group femur. \u003Cstrong\u003E(B)\u003C\u002Fstrong\u003E The diabetic group femur. \u003Cstrong\u003E(C)\u003C\u002Fstrong\u003E The CS group femur. \u003Cstrong\u003E(D)\u003C\u002Fstrong\u003E The Met group femur. \u003Cstrong\u003E(E)\u003C\u002Fstrong\u003E The trabecular separation (Tb·Sp) in different groups. \u003Cstrong\u003E(F)\u003C\u002Fstrong\u003E The femoral thickness (Tb·Th) in different groups. \u003Cstrong\u003E(G)\u003C\u002Fstrong\u003E The percentage of bone trabecular area (BV\u002FTV) in different groups; \u003Csup\u003E##\u003C\u002Fsup\u003Eindicates \u003Ci\u003Ep\u003C\u002Fi\u003E < 0.01 compared with control. **indicates \u003Ci\u003Ep\u003C\u002Fi\u003E < 0.01 compared with the diabetic group. BM. Bone marrow; Tb. Trabecular bone.\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\u003Ch3\u003EChondroitin Sulfate Inhibited Bone Marrow Lipogenesis of Type 1 Diabetic Rats\u003C\u002Fh3\u003E\u003Cp class=\"mb0\"\u003ECompared with the control group, the number of bone marrow adipocytes of diabetic rats increased significantly, and the bone marrow adipocyte density and adipocyte diameter were larger than the control (\u003Ci\u003Ep\u003C\u002Fi\u003E < 0.01) (\u003Ca href=\"#f7\"\u003EFigure 7\u003C\u002Fa\u003E). Ten weeks after CS or metformin treatment, the bone marrow adipocyte density and adipocyte diameter decreased (CS \u003Ci\u003Evs\u003C\u002Fi\u003E. T1DM, \u003Ci\u003Ep\u003C\u002Fi\u003E < 0.01; Met \u003Ci\u003Evs\u003C\u002Fi\u003E. T1DM, \u003Ci\u003Ep\u003C\u002Fi\u003E < 0.01) (\u003Ca href=\"#f7\"\u003EFigure 7\u003C\u002Fa\u003E). The results indicated that CS could inhibit bone marrow lipogenesis of type 1 diabetic rats.\u003C\u002Fp\u003E\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"Imageheaders\"\u003EFIGURE 7\u003C\u002Fdiv\u003E\u003Cdiv class=\"FigureDesc\"\u003E\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g007.jpg\" name=\"\" target=\"_blank\"\u003E\n \u003Cpicture\u003E\n \u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=480&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g007.jpg\" media=\"(max-width: 563px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=370&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g007.jpg\" media=\"(max-width: 1024px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=290&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g007.jpg\" media=\"(max-width: 1441px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=410&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g007.jpg\" media=\"\"\u003E\u003Csource type=\"image\u002Fjpg\" srcset=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g007.jpg\" media=\"\"\u003E \u003Cimg src=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g007.jpg\" alt=\"www.frontiersin.org\" id=\"f7\" loading=\"lazy\"\u003E\n \u003C\u002Fpicture\u003E\n\u003C\u002Fa\u003E\u003Cp\u003E\u003Cstrong\u003EFigure 7\u003C\u002Fstrong\u003E Adipocytes in the bone marrow cavity of the tibia in different groups at the end of the 10th week, H&E staining. \u003Cstrong\u003E(A)\u003C\u002Fstrong\u003E The control group tibia bone marrow. \u003Cstrong\u003E(B)\u003C\u002Fstrong\u003E The diabetic group tibia bone marrow. \u003Cstrong\u003E(C)\u003C\u002Fstrong\u003E The CS group tibia bone marrow. \u003Cstrong\u003E(D)\u003C\u002Fstrong\u003E The Met group tibia bone marrow. \u003Cstrong\u003E(E)\u003C\u002Fstrong\u003E Adipocyte density in different groups. \u003Cstrong\u003E(F)\u003C\u002Fstrong\u003E Adipocyte diameter in different groups. \u003Csup\u003E##\u003C\u002Fsup\u003Eindicates \u003Ci\u003Ep\u003C\u002Fi\u003E < 0.01 compared with control. **indicates \u003Ci\u003Ep\u003C\u002Fi\u003E < 0.01 compared with the diabetic group. Red arrows indicate adipocytes.\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\u003Ch3\u003EChondroitin Sulfate Inhibited Osteoclastogenesis of Type 1 Diabetic Rats\u003C\u002Fh3\u003E\u003Cp class=\"mb0\"\u003EAfter TRAP staining, the osteoclasts were stained purplish red. There was an increased number of femoral osteoclasts in type 1 diabetic group rats compared with control (\u003Ci\u003Ep\u003C\u002Fi\u003E < 0.01) (\u003Ca href=\"#f8\"\u003EFigure 8\u003C\u002Fa\u003E). Ten weeks after CS or metformin treatment, osteoclast number was decreased in the CS or Met group (CS group \u003Ci\u003Evs\u003C\u002Fi\u003E. T1DM group, \u003Ci\u003Ep\u003C\u002Fi\u003E < 0.01; Met group \u003Ci\u003Evs\u003C\u002Fi\u003E. T1DM group, \u003Ci\u003Ep\u003C\u002Fi\u003E < 0.01) (\u003Ca href=\"#f8\"\u003EFigure 8E\u003C\u002Fa\u003E), indicating that CS could inhibit osteoclasts proliferation in type 1 diabetic rats.\u003C\u002Fp\u003E\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"Imageheaders\"\u003EFIGURE 8\u003C\u002Fdiv\u003E\u003Cdiv class=\"FigureDesc\"\u003E\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g008.jpg\" name=\"\" target=\"_blank\"\u003E\n \u003Cpicture\u003E\n \u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=480&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g008.jpg\" media=\"(max-width: 563px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=370&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g008.jpg\" media=\"(max-width: 1024px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=290&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g008.jpg\" media=\"(max-width: 1441px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=410&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g008.jpg\" media=\"\"\u003E\u003Csource type=\"image\u002Fjpg\" srcset=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g008.jpg\" media=\"\"\u003E \u003Cimg src=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g008.jpg\" alt=\"www.frontiersin.org\" id=\"f8\" loading=\"lazy\"\u003E\n \u003C\u002Fpicture\u003E\n\u003C\u002Fa\u003E\u003Cp\u003E\u003Cstrong\u003EFigure 8\u003C\u002Fstrong\u003E The osteoclasts in femoral bone tissues of different groups at the end day of the 10th week. \u003Cstrong\u003E(A)\u003C\u002Fstrong\u003E The femoral bone tissues of control group rat. \u003Cstrong\u003E(B)\u003C\u002Fstrong\u003E The femoral bone tissues of diabetic group rat. \u003Cstrong\u003E(C)\u003C\u002Fstrong\u003E The femoral bone tissues of CS group rat. \u003Cstrong\u003E(D)\u003C\u002Fstrong\u003E The femoral bone tissues of Met group rat. \u003Cstrong\u003E(E)\u003C\u002Fstrong\u003E Number of osteoclasts per unit field in different groups. Bone tissues were stained by TRACP method, osteoclasts are multinucleate cells, and the red arrows point to osteoclasts. \u003Csup\u003E##\u003C\u002Fsup\u003Eindicates \u003Ci\u003Ep\u003C\u002Fi\u003E < 0.01 compared with control. **indicates \u003Ci\u003Ep\u003C\u002Fi\u003E < 0.01 compared with the diabetic group.\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\u003Ch3\u003EChondroitin Sulfate Upregulated OPG and RUNX 2 and Downregulated RANKL Expression in Bone Tissues\u003C\u002Fh3\u003E\u003Cp class=\"mb0\"\u003EPathological analysis showed that bone OPG and RUNX 2 expression levels were lowered in type 1 diabetic rats (T1DM \u003Ci\u003Evs\u003C\u002Fi\u003E. Control, \u003Ci\u003Ep\u003C\u002Fi\u003E < 0.01); RANKL level in bone tissue was higher in type 1 diabetic rats (T1DM \u003Ci\u003Evs\u003C\u002Fi\u003E. Control, \u003Ci\u003Ep\u003C\u002Fi\u003E < 0.01) (\u003Ca href=\"#f9\"\u003EFigure 9\u003C\u002Fa\u003E). After 10 weeks of CS or metformin administration, the bone OPG and RUNX 2 levels increased (CS or Met group \u003Ci\u003Evs\u003C\u002Fi\u003E. T1DM group, \u003Ci\u003Ep\u003C\u002Fi\u003E < 0.01) and the RANKL level decreased (CS or Met \u003Ci\u003Evs\u003C\u002Fi\u003E. T1DM group, \u003Ci\u003Ep\u003C\u002Fi\u003E < 0.01) (\u003Ca href=\"#f9\"\u003EFigures 9A–C\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"Imageheaders\"\u003EFIGURE 9\u003C\u002Fdiv\u003E\u003Cdiv class=\"FigureDesc\"\u003E\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g009.jpg\" name=\"\" target=\"_blank\"\u003E\n \u003Cpicture\u003E\n \u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=480&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g009.jpg\" media=\"(max-width: 563px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=370&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g009.jpg\" media=\"(max-width: 1024px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=290&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g009.jpg\" media=\"(max-width: 1441px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=410&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g009.jpg\" media=\"\"\u003E\u003Csource type=\"image\u002Fjpg\" srcset=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g009.jpg\" media=\"\"\u003E \u003Cimg src=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g009.jpg\" alt=\"www.frontiersin.org\" id=\"f9\" loading=\"lazy\"\u003E\n \u003C\u002Fpicture\u003E\n\u003C\u002Fa\u003E\u003Cp\u003E\u003Cstrong\u003EFigure 9\u003C\u002Fstrong\u003E Immunohistochemical staining of femur and positive staining percentage of OPG, RUNX2, and RANKL in each group. \u003Cstrong\u003E(A)\u003C\u002Fstrong\u003E The positive staining percentage of OPG in the femur of each group. \u003Cstrong\u003E(B)\u003C\u002Fstrong\u003E The positive staining percentage of RUNX 2 in the femur of each group. \u003Cstrong\u003E(C)\u003C\u002Fstrong\u003E The positive staining percentage of RANKL in the femur of each group. \u003Csup\u003E##\u003C\u002Fsup\u003Eindicates \u003Ci\u003Ep\u003C\u002Fi\u003E < 0.01 compared with control. **indicates \u003Ci\u003Ep\u003C\u002Fi\u003E < 0.01 compared with the diabetic group.\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\u003Ca id=\"h5\" name=\"h5\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EDiscussion\u003C\u002Fh2\u003E\u003Cp class=\"mb15\"\u003EDOP is a serious metabolic bone disease associated with diabetes. It has the characteristics of reduced BMD, destruction of bone microstructure, increased brittleness, reduced strength, and easy to fracture, which seriously affects the quality of life of people with diabetes (\u003Ca href=\"#B18\"\u003E18\u003C\u002Fa\u003E, \u003Ca href=\"#B19\"\u003E19\u003C\u002Fa\u003E). Clinical treatment of DOP is to use chemical drugs such as vitamin D3, diphosphonate, calcitonin, and calcium to inhibit bone absorption, promote bone formation, and improve bone mineralization on the premise of controlling blood glucose. However, using chemical drugs long term can also lead to side effects, such as gastrointestinal diseases (\u003Ca href=\"#B20\"\u003E20\u003C\u002Fa\u003E). Therefore, natural anti-osteoporosis drugs are much popular.\u003C\u002Fp\u003E\u003Cp class=\"mb15\"\u003EIn the present study, we used the method of STZ injection to construct a rat model of type 1 diabetes, and intragastric administration of CS for 10 weeks. We detected the BMD, bone micro-CT, and bone pathology, and the results indicated that CS could inhibit bone loss, increase BMD, repair bone microstructure of type 1 diabetic rats, and thus prevent DOP.\u003C\u002Fp\u003E\u003Cp class=\"mb15\"\u003EDOP is closely related to oxidative stress. Hyperglycemia induced reactive oxygen species (ROS) production \u003Ci\u003Ein vivo\u003C\u002Fi\u003E and hindered the proliferation and differentiation of osteoblasts (\u003Ca href=\"#B21\"\u003E21\u003C\u002Fa\u003E–\u003Ca href=\"#B23\"\u003E23\u003C\u002Fa\u003E). It has been confirmed that a sharp increase in the level of ROS induces death of osteoblasts, resulting in bone structure damage and BMD reduction (\u003Ca href=\"#B24\"\u003E24\u003C\u002Fa\u003E). In the present study, we found that the SOD, GPX, and CAT activity levels were upregulated after 10 weeks of CS administration, indicating that CS could inhibit oxidative stress in type 1 diabetic rats; this may be one of important reasons why CS could prevent bone loss in type 1 diabetic rats.\u003C\u002Fp\u003E\u003Cp class=\"mb15\"\u003EInflammation is closely related to osteoporosis, which is another main cause of DOP (\u003Ca href=\"#B25\"\u003E25\u003C\u002Fa\u003E). The level of inflammatory cytokines in diabetes was significantly higher than that in healthy people, and accumulation of inflammatory cytokines could mediate oxidative stress damage, prompting osteoclast proliferation, increasing bone absorption, and thus causing osteoporosis (\u003Ca href=\"#B26\"\u003E26\u003C\u002Fa\u003E). In this study, we found that CS could inhibit the inflammation in type 1 diabetic rats, and inflammatory cytokines were downregulated by CS. Many other natural products have also been reported to relieve DOP through an anti-inflammatory manner (\u003Ca href=\"#B23\"\u003E23\u003C\u002Fa\u003E, \u003Ca href=\"#B27\"\u003E27\u003C\u002Fa\u003E–\u003Ca href=\"#B29\"\u003E29\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\u003Cp class=\"mb15\"\u003EBoth osteoblasts and bone marrow adipocytes were derived from bone marrow mesenchymal stem cells (\u003Ca href=\"#B30\"\u003E30\u003C\u002Fa\u003E). As the number of bone marrow adipocytes increased, that of osteoblasts will decrease. Changes in the number and size of bone marrow adipocytes were positively correlated with osteoporosis, so they were important criteria for evaluating the efficacy of osteoporosis drugs (\u003Ca href=\"#B31\"\u003E31\u003C\u002Fa\u003E–\u003Ca href=\"#B33\"\u003E33\u003C\u002Fa\u003E). In diabetes, hyperglycemia promotes the differentiation of bone marrow adipocytes and inhibits osteoblast differentiation (\u003Ca href=\"#B34\"\u003E34\u003C\u002Fa\u003E). As indicated in the present study, the bone marrow adipocyte number and size in type 1 diabetic rats were higher than those in control group rats, which were downregulated by 10 weeks of CS administration. Our previous study also found that trace elements of zinc, black rice anthocyanin, and lycopene were all having a preventive effect on DOP, and all of them can inhibit bone marrow adipocyte generation (\u003Ca href=\"#B4\"\u003E4\u003C\u002Fa\u003E, \u003Ca href=\"#B23\"\u003E23\u003C\u002Fa\u003E, \u003Ca href=\"#B35\"\u003E35\u003C\u002Fa\u003E), which is consistent with the results of this study.\u003C\u002Fp\u003E\u003Cp class=\"mb15\"\u003EBone tissue structure is an important basis for evaluating bone health (\u003Ca href=\"#B36\"\u003E36\u003C\u002Fa\u003E). In this study, we applied bone micro-CT and bone tissue pathology techniques to evaluate bone structure; the results indicated that CS can improve bone structure lesions caused by diabetes, and it can effectively restore bone morphological parameters and upregulate BMD.\u003C\u002Fp\u003E\u003Cp class=\"mb15\"\u003EThe biochemical markers of bone turnover (BMBT) were metabolite of bone tissue. BMBT includes bone formation and bone resorption markers, which were important indicators for laboratory diagnosis of osteoporosis (\u003Ca href=\"#B37\"\u003E37\u003C\u002Fa\u003E, \u003Ca href=\"#B38\"\u003E38\u003C\u002Fa\u003E). Not only can it quickly reflect the process of bone formation and bone resorption, but it also can be used to reveal pathogenesis of metabolic bone disease, predict the rate of bone loss and fracture risk, and diagnose osteoporosis; at the same time, it can be used to quickly reflect the therapeutic effect of anti-osteoporosis drugs (\u003Ca href=\"#B39\"\u003E39\u003C\u002Fa\u003E). In our present study, the bone formation markers (osteocalcin and ALP) as well as bone resorption markers (TRACP 5b and CTX 1) all increased in type 1 diabetic rats, which indicated that diabetic rats had a higher bone turnover rate. This study showed that CS could downregulate the BMBT in diabetic rats and inhibit the higher bone turnover rate.\u003C\u002Fp\u003E\u003Cp class=\"mb15\"\u003ERANKL was a member of the TNF superfamily involved in immune regulation and bone metabolism, and it was an important activator of osteoclast differentiation and maturation (\u003Ca href=\"#B40\"\u003E40\u003C\u002Fa\u003E). RANKL activates osteoclast differentiation, thus promoting bone resorption by competing with OPG to bind to receptor RANK. Overexpression of RANKL can lead to excessive activation of osteoclasts, which can lead to osteoporosis (\u003Ca href=\"#B41\"\u003E41\u003C\u002Fa\u003E). OPG was also a member of the TNF superfamily. It was highly expressed in testis and bone marrow (\u003Ca href=\"#B42\"\u003E42\u003C\u002Fa\u003E). OPG binds to RANKL and blocks binding of RANKL to RANK. At the same time, OPG can inhibit osteoclast differentiation and maturation, and promote osteoclasts apoptosis (\u003Ca href=\"#B43\"\u003E43\u003C\u002Fa\u003E). When the ratio of OPG to RANKL increases, bone formation activity of osteoblasts increases, and bone metabolism tends to be in a positive balance. When the ratio of OPG to RANKL decreases, the bone resorption activity of osteoclasts increases, and bone metabolism tends to be in a negative balance (\u003Ca href=\"#B44\"\u003E44\u003C\u002Fa\u003E). In the present study, the level of OPG\u002FRANKL ratio in diabetic rats was greatly decreased compared with control, indicating increased bone resorption activity; after 10 weeks of CS treatment, the OPG\u002FRANKL ratio was upregulated, indicating increased bone formation activity. One of the mechanisms of CS against DOP is by upregulating the OPG\u002FRANKL ratio. In this study, we detected the bone OPG, RANKL, and RUNX 2 proteins using an immunohistochemical method, which has the advantage of localizing the protein, but in a quantitative aspect, it is inferior to Western blotting; in subsequent experiments, we will supplement the Western blotting experiment to confirm the above results.\u003C\u002Fp\u003E\u003Cp class=\"mb0\"\u003EAs a first-line drug for diabetes, metformin is a chemically synthesized drug. The main side effects are gastrointestinal reactions, such as nausea and vomiting (\u003Ca href=\"#B45\"\u003E45\u003C\u002Fa\u003E), as well as gut microbiota dysbiosis (\u003Ca href=\"#B46\"\u003E46\u003C\u002Fa\u003E). Secondly, metformin will interfere with the absorption of vitamin B12 and folic acid. Studies have shown that up to 30% of patients taking metformin have B12 deficiency (\u003Ca href=\"#B47\"\u003E47\u003C\u002Fa\u003E, \u003Ca href=\"#B48\"\u003E48\u003C\u002Fa\u003E). In this study, CS showed a good anti-DOP effect, similar to metformin. However, the CS used in this study was naturally extracted and has the advantages of high safety and less side effects compared with metformin. This study revealed the role of CS in DOP treatment through animal experiments. Later, we will further reveal its molecular mechanism through \u003Ci\u003Ein vitro\u003C\u002Fi\u003E cell experiments and further confirm its effect through human experiments.\u003C\u002Fp\u003E\u003Ca id=\"h6\" name=\"h6\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EData Availability Statement\u003C\u002Fh2\u003E\u003Cp class=\"mb0\"\u003EThe original contributions presented in the study are included in the article\u002FSupplementary Material. Further inquiries can be directed to the corresponding authors.\u003C\u002Fp\u003E\u003Ca id=\"h7\" name=\"h7\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EEthics Statement\u003C\u002Fh2\u003E\u003Cp class=\"mb0\"\u003EThe animal study was reviewed and approved by Shaanxi University of Technology Animal Ethics Committee.\u003C\u002Fp\u003E\u003Ca id=\"h8\" name=\"h8\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EAuthor Contributions\u003C\u002Fh2\u003E\u003Cp class=\"mb0\"\u003EStudy design: SQ, HZ, DC, TY, and XL. Study conduct: SQ, HZ, MS, ZS, YH, and SC. Data collection and analysis: SQ, HZ, MS, ZS, YH, and SC. Animal model construction: SQ and HZ. Histopathological experiment: SQ, MS, ZS, and SC. Manuscript draft: SQ. Manuscript revision: HZ. All authors contributed to the article and approved the submitted version.\u003C\u002Fp\u003E\u003Ca id=\"h9\" name=\"h9\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EFunding\u003C\u002Fh2\u003E\u003Cp class=\"mb0\"\u003EThis research was funded by the Postdoctoral Program in Shaanxi University of Technology (SLGBH16-03), “Shaanxi Sanqin Scholar” Innovation Team, the Key Research Projects of Shaanxi Provincial Department of Education (20JY005), Shaanxi University of Technology Project (SLGKY2010), and the Key projects of Shaanxi Science and Technology Department (2021FP-14), and Shaanxi University of Technology Project (SLGKY2004).\u003C\u002Fp\u003E\u003Ca id=\"h10\" name=\"h10\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EConflict of Interest\u003C\u002Fh2\u003E\u003Cp class=\"mb0\"\u003EThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003C\u002Fp\u003E\u003Ca id=\"h11\" name=\"h11\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EPublisher’s Note\u003C\u002Fh2\u003E\u003Cp class=\"mb15\"\u003EAll claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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Owen MD, Baker BC, Scott EM, Forbes K. Interaction Between Metformin, Folate and Vitamin B12 and the Potential Impact on Fetal Growth and Long-Term Metabolic Health in Diabetic Pregnancies. \u003Ci\u003EInt J Mol Sci\u003C\u002Fi\u003E (2021) 11:5759–70. doi: 10.3390\u002Fijms22115759\u003C\u002Fp\u003E\u003Cp class=\"ReferencesCopy2\" style=\"margin-left:1em;\"\u003E\u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.3390\u002Fijms22115759\" target=\"_blank\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"http:\u002F\u002Fscholar.google.com\u002Fscholar_lookup?author=MD+Owen&author=BC+Baker&author=EM+Scott&author=K+Forbes&publication_year=2021&title=Interaction%20Between%20Metformin%2C%20Folate%20and%20Vitamin%20B12%20and%20the%20Potential%20Impact%20on%20Fetal%20Growth%20and%20Long-Term%20Metabolic%20Health%20in%20Diabetic%20Pregnancies&journal=Int+J+Mol+Sci&volume=11&pages=5759-70\" target=\"_blank\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"thinLineM20\"\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"AbstractSummary\"\u003E\u003Cp\u003E\u003Cspan\u003EKeywords:\u003C\u002Fspan\u003E chondroitin sulfate, diabetes, osteoporosis, bone microstructure, bone metabolism\u003C\u002Fp\u003E\u003Cp\u003E\u003Cspan\u003ECitation:\u003C\u002Fspan\u003E Qi SS, Shao ML, Sun Z, Chen SM, Hu YJ, Li XS, Chen DJ, Zheng HX and Yue TL (2021) Chondroitin Sulfate Alleviates Diabetic Osteoporosis and Repairs Bone Microstructure \u003Ci\u003Evia\u003C\u002Fi\u003E Anti-Oxidation, Anti-Inflammation, and Regulating Bone Metabolism. \u003Ci\u003EFront. Endocrinol.\u003C\u002Fi\u003E 12:759843. doi: 10.3389\u002Ffendo.2021.759843\u003C\u002Fp\u003E\u003Cp id=\"timestamps\"\u003E\u003Cspan\u003EReceived:\u003C\u002Fspan\u003E 17 August 2021; \u003Cspan\u003EAccepted:\u003C\u002Fspan\u003E 29 September 2021;\u003Cbr\u003E\u003Cspan\u003EPublished:\u003C\u002Fspan\u003E 27 October 2021.\u003C\u002Fp\u003E\u003Cdiv\u003E\u003Cp\u003EEdited by:\u003C\u002Fp\u003E\u003Ca href=\"https:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F42129\"\u003EPeter Vestergaard\u003C\u002Fa\u003E, Aalborg University Hospital, Denmark\u003C\u002Fdiv\u003E\u003Cdiv\u003E\u003Cp\u003EReviewed by:\u003C\u002Fp\u003E\u003Ca href=\"https:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F742646\"\u003EGanesan Ramamoorthi\u003C\u002Fa\u003E, Moffitt Cancer Center, United States\u003Cbr\u003E\u003Ca href=\"https:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F663338\"\u003EYaguang Li\u003C\u002Fa\u003E, Central South University, China\u003Cbr\u003E\u003Ca href=\"https:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F1423801\"\u003EChen Chen\u003C\u002Fa\u003E, Shaanxi University of Science and Technology, China\u003C\u002Fdiv\u003E\u003Cp\u003E\u003Cspan\u003ECopyright\u003C\u002Fspan\u003E © 2021 Qi, Shao, Sun, Chen, Hu, Li, Chen, Zheng and Yue. This is an open-access article distributed under the terms of the \u003Ca rel=\"license\" href=\"http:\u002F\u002Fcreativecommons.org\u002Flicenses\u002Fby\u002F4.0\u002F\" target=\"_blank\"\u003ECreative Commons Attribution License (CC BY)\u003C\u002Fa\u003E. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\u003C\u002Fp\u003E\u003Cp\u003E\u003Cspan\u003E*Correspondence:\u003C\u002Fspan\u003E Tian Li Yue, \u003Ca id=\"encmail\"\u003EeXVldGxAbndhZnUuZWR1LmNu\u003C\u002Fa\u003E; Hong Xing Zheng, \u003Ca id=\"encmail\"\u003Eemhlbmdob25neGluZ0BzbnV0LmVkdS5jbg==\u003C\u002Fa\u003E; De Jing Chen, \u003Ca id=\"encmail\"\u003EY2Rqc2xnQDEyNi5jb20=\u003C\u002Fa\u003E\u003C\u002Fp\u003E\u003Cdiv class=\"clear\"\u003E\u003C\u002Fdiv\u003E\u003C\u002Fdiv\u003E",menuHtml:"\u003Cul class=\"flyoutJournal\"\u003E\u003Cli\u003E\u003Ca href=\"#h1\"\u003EAbstract\u003C\u002Fa\u003E\u003C\u002Fli\u003E\u003Cli\u003E\u003Ca href=\"#h2\"\u003EIntroduction\u003C\u002Fa\u003E\u003C\u002Fli\u003E\u003Cli\u003E\u003Ca href=\"#h3\"\u003EMaterials and Methods\u003C\u002Fa\u003E\u003C\u002Fli\u003E\u003Cli\u003E\u003Ca href=\"#h4\"\u003EResults\u003C\u002Fa\u003E\u003C\u002Fli\u003E\u003Cli\u003E\u003Ca href=\"#h5\"\u003EDiscussion\u003C\u002Fa\u003E\u003C\u002Fli\u003E\u003Cli\u003E\u003Ca href=\"#h6\"\u003EData Availability Statement\u003C\u002Fa\u003E\u003C\u002Fli\u003E\u003Cli\u003E\u003Ca href=\"#h7\"\u003EEthics Statement\u003C\u002Fa\u003E\u003C\u002Fli\u003E\u003Cli\u003E\u003Ca href=\"#h8\"\u003EAuthor Contributions\u003C\u002Fa\u003E\u003C\u002Fli\u003E\u003Cli\u003E\u003Ca href=\"#h9\"\u003EFunding\u003C\u002Fa\u003E\u003C\u002Fli\u003E\u003Cli\u003E\u003Ca href=\"#h10\"\u003EConflict of Interest\u003C\u002Fa\u003E\u003C\u002Fli\u003E\u003Cli\u003E\u003Ca href=\"#h11\"\u003EPublisher’s Note\u003C\u002Fa\u003E\u003C\u002Fli\u003E\u003Cli\u003E\u003Ca href=\"#h12\"\u003EReferences\u003C\u002Fa\u003E\u003C\u002Fli\u003E\u003C\u002Ful\u003E"},files:[{name:"EPUB.epub",fileServerPackageEntryId:e,type:{code:aH,name:aH}},{name:R,fileServerPackageEntryId:R,type:{code:v,name:v}},{name:R,fileServerPackageEntryId:e,type:{code:v,name:v}},{name:aI,fileServerPackageEntryId:aI,type:{code:"NLM_XML",name:"XML"}},{name:"Provisional PDF.pdf",fileServerPackageEntryId:e,type:{code:v,name:v}}]},currentArticlePageMetaInfo:{title:aJ,link:[{rel:"canonical",href:aK}],meta:[{hid:C,property:C,name:C,content:aL},{hid:aM,property:aM,name:"title",content:aJ},{hid:aN,property:aN,name:C,content:aL},{hid:aO,name:aO,content:"chondroitin sulfate,diabetes,Osteoporosis,Bone microstructure,bone metabolism"},{hid:aP,property:aP,name:"site_name",content:D},{hid:aQ,property:aQ,name:J,content:"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=1200&f=png\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F759843\u002Ffendo-12-759843-HTML\u002Fimage_m\u002Ffendo-12-759843-g001.jpg"},{hid:aR,property:aR,name:"type",content:"article"},{hid:aS,property:aS,name:"url",content:aK},{hid:aT,name:aT,content:"summary_large_image"},{hid:aU,name:aU,content:"12"},{hid:aV,name:aV,content:t},{hid:aW,name:aW,content:D},{hid:aX,name:aX,content:L},{hid:aY,name:aY,content:M},{hid:aZ,name:aZ,content:af},{hid:a_,name:a_,content:"759843"},{hid:a$,name:a$,content:"English"},{hid:ba,name:ba,content:ag},{hid:bb,name:bb,content:"chondroitin sulfate; diabetes; Osteoporosis; Bone microstructure; bone metabolism"},{hid:bc,name:bc,content:ah},{hid:bd,name:bd,content:"https:\u002F\u002Fwww.frontiersin.org\u002Fjournals\u002Fendocrinology\u002Farticles\u002F10.3389\u002Ffendo.2021.759843\u002Fpdf"},{hid:be,name:be,content:"2021\u002F09\u002F29"},{hid:bf,name:bf,content:"2021\u002F10\u002F27"},{hid:"citation_author_0",name:o,content:"Qi, Shan Shan"},{hid:"citation_author_institution_0",name:p,content:bg},{hid:"citation_author_1",name:o,content:"Shao, Meng Li"},{hid:"citation_author_institution_1",name:p,content:s},{hid:"citation_author_2",name:o,content:"Sun, Ze"},{hid:"citation_author_institution_2",name:p,content:s},{hid:"citation_author_3",name:o,content:"Chen, Si Min"},{hid:"citation_author_institution_3",name:p,content:s},{hid:"citation_author_4",name:o,content:"Hu, Ying Jun"},{hid:"citation_author_institution_4",name:p,content:s},{hid:"citation_author_5",name:o,content:"Li, Xin Sheng"},{hid:"citation_author_institution_5",name:p,content:s},{hid:"citation_author_6",name:o,content:"Chen, De Jing"},{hid:"citation_author_institution_6",name:p,content:s},{hid:"citation_author_7",name:o,content:"Zheng, Hong Xing"},{hid:"citation_author_institution_7",name:p,content:s},{hid:"citation_author_8",name:o,content:"Yue, Tian 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of Technology",2,"College of Biological Science and Engineering, Shaanxi University of Technology, China","Frontiers in Endocrinology","endocrinology","PDF",5,106,"Chen","Link",4,"Qinba State Key Laboratory of Biological Resources and Ecological Environment","description","Frontiers","Help center","Grey","Medium","ssph-journal.org","fship","image","landscape","Front. Endocrinol.","1664-2392",void 0,11,18,12,"fendo-12-759843.pdf",1920,"por-journal.com",7,"escubed.org",1918,"fipp","https:\u002F\u002Fd2csxpduxe849s.cloudfront.net\u002Fmedia\u002FE32629C6-9347-4F84-81FEAEF7BFA342B3\u002F1AAA1237-EA54-405E-B5292056FC2FC63E\u002Fwebimage-52CDCF24-D906-45A5-AFA5AA6D3AD70D22.png","histology","medicine","22C10171-81B3-4DA6-99342F272A32E8BB","jpg","2022-06-27T09:59:30Z","fendo",23,"journal_field","10.3389\u002Ffendo.2021.759843","Chondroitin Sulfate Alleviates Diabetic Osteoporosis and Repairs Bone Microstructure via Anti-Oxidation, Anti-Inflammation, and Regulating Bone Metabolism","\u003Cp\u003EDiabetic osteoporosis (DOP) belongs to secondary osteoporosis caused by diabetes; it has the characteristics of high morbidity and high disability. In the present study, we constructed a type 1 diabetic rat model and administered chondroitin sulfate (200 mg\u002Fkg) for 10 weeks to observe the preventive effect of chondroitin sulfate on the bone loss of diabetic rats. The results showed that chondroitin sulfate can reduce blood glucose and relieve symptoms of diabetic rats; in addition, it can significantly increase the bone mineral density, improve bone microstructure, and reduce bone marrow adipocyte number in diabetic rats; after 10 weeks of chondroitin sulfate administration, the SOD activity level was upregulated, as well as CAT levels, indicating that chondroitin sulfate can alleviate oxidative stress in diabetic rats. Chondroitin sulfate was also found to reduce the level of serum inflammatory cytokines (TNF-α, IL-1, IL-6, and MCP-1) and alleviate the inflammation in diabetic rats; bone metabolism marker detection results showed that chondroitin sulfate can reduce bone turnover in diabetic rats (decreased RANKL, CTX-1, ALP, and TRACP 5b levels were observed after 10 weeks of chondroitin sulfate administration). At the same time, the bone OPG and RUNX 2 expression levels were higher after chondroitin sulfate treatment, the bone RANKL expression was lowered, and the OPG\u002FRANKL ratio was upregulated. All of the above indicated that chondroitin sulfate could prevent STZ-induced DOP and repair bone microstructure; the main mechanism was through anti-oxidation, anti-inflammatory, and regulating bone metabolism. Chondroitin sulfate could be used to develop anti-DOP functional foods and diet interventions for diabetes.\u003C\u002Fp\u003E",889583,"Shan Shan","College of Food Science and Engineering, Northwest Agriculture and Forestry (A&F) University","Meng Li","Ze","Si Min","Ying Jun","Xin Sheng","Li","Shaanxi Key Laboratory of Resource Biology","De Jing",1397318,"Hong Xing","Tian Li",42129,"Peter",663338,"Yaguang",742646,"Ganesan",1423801,{},107,"Clinical Diabetes","clinical-diabetes","EPUB","fendo-12-759843.xml","Frontiers | Chondroitin Sulfate Alleviates Diabetic Osteoporosis and Repairs Bone Microstructure via Anti-Oxidation, Anti-Inflammation, and Regulating Bone Metabolism","https:\u002F\u002Fwww.frontiersin.org\u002Fjournals\u002Fendocrinology\u002Farticles\u002F10.3389\u002Ffendo.2021.759843\u002Ffull","Diabetic osteoporosis (DOP) belongs to secondary osteoporosis caused by diabetes; it has the characteristics of high morbidity and high disability. 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