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褪黑素促进骨再生作用机制的研究进展(下)_CPHI制药在线
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href="/Products/list-htm-catid-79.html"> 抗肿瘤制剂</a> <a href="/Products/list-htm-catid-80.html"> 抗寄生虫制剂</a> <a href="/Products/list-htm-catid-81.html"> 抗过敏用制剂</a> <a href="/Products/list-htm-catid-82.html"> 抗菌药与抗病毒药制剂</a> <a href="/Products/list-htm-catid-83.html"> 抗结核及麻风制剂</a> <a href="/Products/list-htm-catid-84.html"> 皮肤科制剂</a> <a href="/Products/list-htm-catid-85.html"> 五官科制剂</a> <a href="/Products/list-htm-catid-86.html"> 消化系统制剂</a> <a href="/Products/list-htm-catid-87.html"> 呼吸系统制剂</a> <a href="/Products/list-htm-catid-88.html"> 循环系统制剂</a> <a href="/Products/list-htm-catid-89.html"> 神经系统类制剂</a> <a href="/Products/list-htm-catid-90.html"> 血液系统药制剂</a> <a href="/Products/list-htm-catid-91.html"> 泌尿与生殖系统制剂</a> <a href="/Products/list-htm-catid-93.html"> 调节免疫功能制剂</a> <a href="/Products/list-htm-catid-94.html"> 调节水、电解质及酸碱平衡制剂</a> <a href="/Products/list-htm-catid-95.html"> 维生素、矿物质与氨基酸类制剂</a> <a href="/Products/list-htm-catid-96.html"> 酶类及其它生化制剂</a> <a href="/Products/list-htm-catid-97.html"> 解热镇痛类制剂</a> <a href="/Products/list-htm-catid-98.html"> 滋补营养药</a> <a href="/Products/list-htm-catid-99.html"> 有关激素类药</a> <a href="/Products/list-htm-catid-100.html"> 内分泌及代谢类制剂</a> <a href="/Products/list-htm-catid-101.html"> 清热解毒制剂</a> <a href="/Products/list-htm-catid-102.html"> 心脑血管类制剂</a> <a href="/Products/list-htm-catid-103.html"> 其它药品制剂</a> </div> <div class="list_list_img"> </div> </div> </li> <li> <span> <a href="/Products/list-htm-catid-104.html"> 药用辅料</a> </span> <div class="list_list"> <div class="title"> <a href="/Products/list-htm-catid-104.html" target="_blank">药用辅料</a> </div> <div class="list_list_item"> <a href="/Products/list-htm-catid-105.html"> 赋形剂</a> <a href="/Products/list-htm-catid-106.html"> 崩解剂</a> <a href="/Products/list-htm-catid-107.html"> 润滑剂</a> <a href="/Products/list-htm-catid-108.html"> 助流剂</a> <a href="/Products/list-htm-catid-109.html"> 包衣材料</a> <a href="/Products/list-htm-catid-110.html"> 增塑剂</a> <a href="/Products/list-htm-catid-111.html"> 肠溶材料</a> <a href="/Products/list-htm-catid-112.html"> 表面活性剂</a> <a href="/Products/list-htm-catid-113.html"> 溶媒</a> <a href="/Products/list-htm-catid-114.html"> 抗氧剂</a> <a href="/Products/list-htm-catid-115.html"> 遮光剂</a> <a href="/Products/list-htm-catid-116.html"> 矫味剂</a> <a href="/Products/list-htm-catid-117.html"> 甜味剂</a> <a href="/Products/list-htm-catid-118.html"> 香精</a> <a href="/Products/list-htm-catid-119.html"> 着色剂</a> <a href="/Products/list-htm-catid-120.html"> 促透剂</a> <a href="/Products/list-htm-catid-121.html"> 助滤剂</a> <a href="/Products/list-htm-catid-122.html"> 澄清剂</a> <a href="/Products/list-htm-catid-123.html"> 防腐剂</a> <a href="/Products/list-htm-catid-124.html"> 稳定剂</a> <a href="/Products/list-htm-catid-125.html"> ＰＨ调节剂</a> <a href="/Products/list-htm-catid-126.html"> 催化剂</a> <a href="/Products/list-htm-catid-127.html"> 其他药用辅料</a> <a href="/Products/list-htm-catid-1039.html"> 推进剂</a> </div> <div class="list_list_img"> </div> 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</div> </div> <div class="newList_route"> <div class="content"> <a href="/">CPHI制药在线</a> <label>></label> <a href="/news/">资讯</a> <label>></label> <a href="/news/category/712">小泥沙</a> <label>></label> <a href="javascript:;">褪黑素促进骨再生作用机制的研究进展(下)</a> <label>></label> </div> </div> <div class="newsDetail"> <div class="content flex_between"> <input id="newsId" type="hidden" value="283105"/> <div class="newsDetail_article"> <div class="zixun-contain"> <h1 class="newsDetail_article_title">褪黑素促进骨再生作用机制的研究进展(下)</h1> <div class="newsDetail_article_create flex_between"> <div class="exam_news_createlocal"> 热门推荐： <a href="/news/search-htm-txtSearch-褪黑素-hide_search-4.html">褪黑素</a> <label>,</label> <a href="/news/search-htm-txtSearch-破骨细胞-hide_search-4.html">破骨细胞</a> <label>,</label> <a href="/news/search-htm-txtSearch-骨再生-hide_search-4.html">骨再生</a> <label>,</label> </div> <div class="exam_news_createtime" style="display: flex"> <div>作者：小泥沙  来源：CPHI制药在线</div>   2025-03-26</div> </div> <div class="news-brief"> 本文继续介绍褪黑素在骨再生领域的作用机制，包括对成骨细胞凋亡和铁死亡的影响、对破骨细胞的作用机制以及促进血管生成的作用，展现其在骨再生研究中的重要价值。 </div> <div class="newsDetail_article_content"> <p style="text-align: center;"><img src="https://cimg.cphi.cn/img_Cphi_cn/image/2025/02/21/13_44_41.png" alt="褪黑素" width="400" height="170" /></p> <p><strong>系列文章推荐：</strong></p> <p><a href="https://www.cphi.cn/news/show-283101.html" target="_blank" rel="noopener"><strong>褪黑素促进骨再生作用机制的研究进展（上）</strong></a></p> <p>上文中，我们介绍了<a href="https://www.cphi.cn/news/show-283101.html" target="_blank" rel="noopener"><strong>褪黑素</strong></a>促进骨再生作用的抗炎和抗氧化作用以及在成骨细胞分化和自噬的作用，本文继续介绍褪黑素与成骨细胞凋亡和铁死亡的关系以及对破骨细胞的作用机制和促进血管生成的作用。</p> <p><strong>③褪黑素与成骨细胞凋亡</strong></p> <p>研究表明，褪黑素对成骨细胞凋亡的影响具有两面性，且与褪黑素浓度密切相关。实验发现使用高糖培养成骨细胞48h后细胞的凋亡率为40.8%，凋亡蛋白cleaved caspase 3的表达升高，而加入褪黑素后细胞凋亡率为28.3%，cleaved caspase 3的表达降低。这与另外两项研究实验结果相似，褪黑素干预后成骨细胞早期凋亡率、总死亡率以及Bax、caspase-3等凋亡相关蛋白的表达明显降低。研究表明，褪黑素可以缓解并改善成骨细胞的凋亡水平，进一步分析发现其与抑制成骨细胞氧化应激密切相关。褪黑素干预后可使枸橼酸铁铵和铝作用成骨细胞造成ROS蓄积的结果得到缓解，使 ROS水平降低。研究表明褪黑素可使核因子红细胞2相关因子2（Nrf2）途径相关蛋白Nrf-2及HO-1表达进一步的增加。Nrf-2是人抗氧化反应元件（ARE）的正向调节因子，Nrf-2通路的激活可以调节细胞内大量抗氧化基因产物的表达水平，并降低氧化应激水平，从而使凋亡水平降低，说明褪黑素抑制成骨细胞的凋亡水平，可能与通过Nrf-2途径抑制成骨细胞的氧化应激水平有关。</p> <p>另有研究表明使用高浓度褪黑素干预成骨细胞，介导内质网应激（ERS）、调节STIM1，导致Septin4、Septin7表达增加以及细胞膜钙升高，成骨细胞过量表达Septin4，可使细胞骨架破坏、细胞形态改变和细胞数量减少。这可能与细胞膜钙升高，通过ERK途径诱导成骨细胞都会使成骨细胞的凋亡明显增加有关。</p> <p><strong>④褪黑素与成骨细胞铁死亡</strong></p> <p>铁死亡是一种铁依赖性的细胞死亡方式，是由于细胞内脂质过氧化、谷胱甘肽过氧化物酶4（GPX4）抗氧化系统失调以及铁超负荷所致，主要特征是细胞内活性氧的堆积和线粒体形态、膜电位的改变。多项研究表明，褪黑素对成骨细胞的铁死亡具有抑制作用，且此作用与褪黑素改善成骨细胞氧化应激以及铁自噬密切相关。首先，褪黑素通过调节Nrf2/HO-1、Wnt以及PI3K/AKT/GSK-3β/P70S6k信号通路使成骨细胞氧化应激水平降低，从而抑制铁死亡。研究表明褪黑素可以使高糖诱导成骨细胞发生铁死亡导致的GPX4和胱氨酸⁃谷氨酸逆向转运蛋白（SLC7A11）表达下调得到逆转，从而抑制成骨细胞的铁死亡。同时研究人员检测核因子红细胞2相关因子2（Nrf2）和血红素加氧酶⁃1（HO-1）的表达水平，结果显示在褪黑素组中的表达水平明显高于高糖组，而在使用Nrf2⁃SiRNA干扰后，褪黑素对成骨细胞铁死亡的改善作用则受到明显抑制，这说明其中Nrf2/HO-1通路起着重要作用。值得注意的是，实验发现铁剂量依赖性下调Wnt靶基因以及PI3K/AKT/GSK-3β/P70S6k 信号通路相关基因的转录与表达，抑制其信号传导，生成ROS和脂质过氧化产物（LPO）。在使用褪黑素后可逆转铁抑制的典型 Wnt及PI3K/AKT/GSK-3β /P70S6k 信号转导，减少ROS和LPO的产生，改善氧化应激，预防铁死亡，恢复铁死亡对成骨细胞分化的抑制作用。其次，褪黑素可以调节miR-550a-3p/ELAVL1轴，改善铁自噬来抑制成骨细胞的铁死亡。ELAV样蛋白1 （ELAVL1） 是一种RNA结合蛋白，能够介导铁自噬，使铁蛋白降解，氧化应激水平升高，从而引起铁死亡。 通过双荧光素酶检测发现miR-550a-3p能够靶向作用于ELAVL1，褪黑素干预高糖培养成骨细胞后miR-550a-3p表达上调，调控ELAVL1表达下调，减少铁自噬的发生，从而使铁死亡得到抑制。根据上述实验结果可知，褪黑素显著降低成骨细胞的铁死亡水平是通过激活 Nrf2/HO-1通路、恢复Wnt及PI3K/AKT/GSK-3β/P70S6k信号通路传导、上调miR-550a-3p，降低ELAVL1相关铁自噬蛋白的表达实现的。</p> <p><strong>3、褪黑素对破骨细胞的作用机制 </strong></p> <p>骨再生的控制不仅需要成骨细胞的调节，还需要破骨细胞的参与。破骨细胞源于造血干细胞，核因子κB 受体活化因子配体/核因子κB 受体活化因子(receptor actvator of nuclear factor-κBligand/receptor actvator of nuclear factor-κB，RANKL/RANK)通路的活化诱导破骨细胞的形成。骨保护素是基质细胞产生的诱饵受体，与 RANKL 结合并阻止其与 RANK 的相互作用。同时，巨噬细胞集落刺激因子促进破骨细胞前体的增殖和破骨细胞的存活。</p> <p>褪黑素减少与骨吸收增加有关，提示褪黑素可能是一种内源性破骨细胞抑制剂。血清中的低褪黑素水平与骨质疏松症患者的低骨密度也表现出相关性。通过抑制 MT2 受体依赖的核因子κB信号通路促进间充质干细胞的成骨分化，并由 RANKL旁分泌下调破骨细胞的生成，表明褪黑素可能通过骨保护素/RANKL/RANK 轴影响成骨细胞系细胞和破骨细胞系细胞之间的相互作用。另有研究报道是褪黑素下调核因子κB 信号通路和活化 T 细胞核因子c-1 (NFATc1) 转录因子直接抑制破骨细胞的分化，而不涉及褪黑素受体。此外，褪黑素还上调骨细胞分泌降钙素发挥对破骨细胞的抑制作用。在细胞水平上，褪黑素抑制 RAW 264.7 细胞在低浓度RANKL 和巨噬细胞集落刺激因子诱导下分化为破骨细胞。</p> <p><strong>4、褪黑素具有促进血管生成的作用 </strong></p> <p>骨修复需要血液供应和血运重建来恢复受损区域，血管化是骨再生的前提和关键环节。褪黑素促进血管生成的机制是通过上调血管内 皮生长因子水平促进骨髓间充质干细胞介导的血管生成，即促进骨生成-血管生成偶联。将骨髓间充质干细胞经褪黑素处理，在得到具有更高表达水平的成骨相关标志物的同时，也得到更高表达水平的血管生成相关标志物，如血管内 皮生长因子、血管生成素2和血管生成素4。褪黑素纳米复合支架的成功制备，实现了褪黑素的长效缓释和成骨能力的增强。将褪黑素包埋丝素电纺丝 (melatonin-encapsuled silk Fibronin electrospun，SF@MT) 纳米纤维植入大鼠临界尺寸的颅骨缺损中，通过激活 <a href="https://www.cphi.cn/news/show-187343.html" target="_blank" rel="noopener"><strong>PI3K/Akt</strong></a>信号通路，可显著促进骨基质沉积和新血管形成。负载褪黑素的纳米纤维海绵支架 (Scaffold@MT) 的植入也显著改善了大鼠股骨远端缺损的血管化骨再生。通过核因子红系2 相关因子 2(nuclear factor-erythroid 2-Related Factor 2,Nrf2)/血红素加氧酶1(heme oxygenase，HO-1) 信号通路，褪黑素纳米复合支架可减少血管内皮细胞的氧化应激损伤以及直接刺激血管内 皮生长因子的产生，从而逆转糖尿病条件下骨生成-血管生成的解偶联并促进成骨。相关的骨组织工程的进展进一步证实褪黑素具有改善缺血组织血管生成的潜力，进而加速骨修复。不过，也有研究指出，在肿瘤、年龄相关性眼病和低氧环境中，褪黑素抑制组织内新血管生成，这与骨愈合过程中的观察结果相矛盾。</p> <p><strong>参考资料</strong></p> <p>[1]王颖,郝楠,谢戬芳.褪黑素在骨关节炎中作用机制的研究进展[J].安徽医学,2024,45(06):794-797.</p> <p>[2]季明意,季欣意,徐俊峰.褪黑素促进骨再生机制及在口腔种植中的应用[J].中国组织工程研究,2025,29(18):3868-3876.</p> <p>[3]李富华,张锦玉.褪黑素对成骨细胞作用机制的研究进展[J].中国骨质疏松杂志,2024,30(11):1678-1682.</p> <p><strong>作者简介：</strong>小泥沙，食品科技工作者，食品科学硕士，现就职于国内某大型药物研发公司，从事营养食品的开发与研究。</p> </div> <div class="newsDetail_article_others"> <div class="yuanchuang"> <label>版权所有，未经允许，不得转载。</label> </div> </div> </div> <div class="xiangguantuijian" style="margin-top: 30px;border-bottom: none;"> <div class="xiangguantuijian_title"> <div class="tuijian_title_left"> <div class="tuijian_title_type"></div> <div class="tuijian_title_text">相关文章</div> </div> </div> <div class="about_article_list"> </div> </div> </div> <div class="newsDetail_info"> <div class="zhuanlaninfo_box"> <div class="zhuanlaninfo_box_info"> <a href="/news/category/712/"><img class="zhuanlaninfo_box_img" src="https://cimg.cphi.cn/img_Cphi_cn/image/2024/05/22/13_44_55.png " alt=""></a> <a href="/news/category/712/"> <div class="zhuanlaninfo_box_name">小泥沙</div> </a> <div class="limit-3 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