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window.loswp.willEdgeCache = false; window.loswp.work = {"work":{"id":5119057,"created_at":"2013-11-16T02:24:59.746-08:00","from_world_paper_id":120819195,"updated_at":"2025-02-01T00:11:20.835-08:00","_data":{"ai_title_tag":"NFκB Inhibition Reverses Osteosarcoma in Saos-2","grobid_abstract":"Beyond a pivotal role in neoplastic transformation and malignant progression, NFjB is intricately involved in bone biology, pointed up by the osteopetrotic phenotype of NFjB (p50-p52) double knock-out mice. Osteopetrosis results from intrinsic defects in osteoclastogenesis, loss of osteoclast bone resorptive activity and, questionably, increased osteoblast activity (bone matrix apposition and mineralization). We here report that inhibition of NFjB signaling activity in Saos-2 cells results in a marked decrease in cellular proliferation, assessed by the incorporation of radioactive thymidine into cellular DNA. Decreased cellular proliferation was accompanied by the induction of bone morphogenic proteins (BMP) 4, 7, and the osteoblast specific transciption factor, Cbfa1, heralding osteoblast differentiation, given the induction of alkaline phosphatase, osteopontin, and osteocalcin message levels and the attendant increase in matrix deposition and mineralization in vitro. These results point to the negative regulation of osteoblast differentiation by NFjB, with implications in the pathogenesis and progression of osteosarcomas. Ó","publication_date":"2002,,","publication_name":"Biochemical and Biophysical Research Communications","grobid_abstract_attachment_id":"49442107"},"document_type":"paper","pre_hit_view_count_baseline":null,"quality":"high","language":"en","title":"Malignant reversion of a human osteosarcoma cell line, Saos-2, by inhibition of NFκB","broadcastable":true,"draft":null,"has_indexable_attachment":true,"indexable":true}}["work"]; window.loswp.workCoauthors = [6855484]; window.loswp.locale = "en"; window.loswp.countryCode = "SG"; window.loswp.cwvAbTestBucket = ""; window.loswp.designVariant = "ds_vanilla"; window.loswp.fullPageMobileSutdModalVariant = "control"; window.loswp.useOptimizedScribd4genScript = false; window.loginModal = {}; window.loginModal.appleClientId = 'edu.academia.applesignon'; window.userInChina = "false";</script><script defer="" src="https://accounts.google.com/gsi/client"></script><div class="ds-loswp-container"><div class="ds-work-card--grid-container"><div class="ds-work-card--container js-loswp-work-card"><div class="ds-work-card--cover"><div class="ds-work-cover--wrapper"><div class="ds-work-cover--container"><button class="ds-work-cover--clickable js-swp-download-button" data-signup-modal="{"location":"swp-splash-paper-cover","attachmentId":49442107,"attachmentType":"pdf"}"><img alt="First page of “Malignant reversion of a human osteosarcoma cell line, Saos-2, by inhibition of NFκB”" class="ds-work-cover--cover-thumbnail" src="https://0.academia-photos.com/attachment_thumbnails/49442107/mini_magick20190131-17760-1nrfog1.png?1548969222" /><img alt="PDF Icon" class="ds-work-cover--file-icon" src="//a.academia-assets.com/images/single_work_splash/adobe_icon.svg" /><div class="ds-work-cover--hover-container"><span class="material-symbols-outlined" style="font-size: 20px" translate="no">download</span><p>Download Free PDF</p></div><div class="ds-work-cover--ribbon-container">Download Free PDF</div><div class="ds-work-cover--ribbon-triangle"></div></button></div></div></div><div class="ds-work-card--work-information"><h1 class="ds-work-card--work-title">Malignant reversion of a human osteosarcoma cell line, Saos-2, by inhibition of NFκB</h1><div class="ds-work-card--work-authors ds-work-card--detail"><a class="ds-work-card--author js-wsj-grid-card-author ds2-5-body-md ds2-5-body-link" data-author-id="6855484" href="https://independent.academia.edu/VAndela"><img alt="Profile image of Valentine Andela" class="ds-work-card--author-avatar" src="//a.academia-assets.com/images/s65_no_pic.png" />Valentine Andela</a></div><div class="ds-work-card--detail"><p class="ds-work-card--detail ds2-5-body-sm">2002, Biochemical and Biophysical Research Communications</p><div class="ds-work-card--work-metadata"><div class="ds-work-card--work-metadata__stat"><span class="material-symbols-outlined" style="font-size: 20px" translate="no">visibility</span><p class="ds2-5-body-sm" id="work-metadata-view-count">…</p></div><div class="ds-work-card--work-metadata__stat"><span class="material-symbols-outlined" style="font-size: 20px" translate="no">description</span><p class="ds2-5-body-sm">5 pages</p></div><div class="ds-work-card--work-metadata__stat"><span class="material-symbols-outlined" style="font-size: 20px" translate="no">link</span><p class="ds2-5-body-sm">1 file</p></div></div><script>(async () => { const workId = 5119057; 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if (!viewCountBody) { throw new Error('Failed to find work views element'); } viewCountBody.textContent = `${commaizedViewCount} views`; } catch (error) { // Remove the whole views element if there was some issue parsing. document.getElementById('work-metadata-view-count')?.parentNode?.remove(); throw new Error(`Failed to parse view count: ${viewCount}`, error); } }; // If the DOM is still loading, wait for it to be ready before updating the view count. if (document.readyState === "loading") { document.addEventListener('DOMContentLoaded', () => { updateViewCount(viewCount); }); // Otherwise, just update it immediately. } else { updateViewCount(viewCount); } })();</script></div><p class="ds-work-card--work-abstract ds-work-card--detail ds2-5-body-md">Beyond a pivotal role in neoplastic transformation and malignant progression, NFjB is intricately involved in bone biology, pointed up by the osteopetrotic phenotype of NFjB (p50-p52) double knock-out mice. Osteopetrosis results from intrinsic defects in osteoclastogenesis, loss of osteoclast bone resorptive activity and, questionably, increased osteoblast activity (bone matrix apposition and mineralization). We here report that inhibition of NFjB signaling activity in Saos-2 cells results in a marked decrease in cellular proliferation, assessed by the incorporation of radioactive thymidine into cellular DNA. Decreased cellular proliferation was accompanied by the induction of bone morphogenic proteins (BMP) 4, 7, and the osteoblast specific transciption factor, Cbfa1, heralding osteoblast differentiation, given the induction of alkaline phosphatase, osteopontin, and osteocalcin message levels and the attendant increase in matrix deposition and mineralization in vitro. These results point to the negative regulation of osteoblast differentiation by NFjB, with implications in the pathogenesis and progression of osteosarcomas. Ó</p><div class="ds-work-card--button-container"><button class="ds2-5-button js-swp-download-button" data-signup-modal="{"location":"continue-reading-button--work-card","attachmentId":49442107,"attachmentType":"pdf","workUrl":"https://www.academia.edu/5119057/Malignant_reversion_of_a_human_osteosarcoma_cell_line_Saos_2_by_inhibition_of_NF%CE%BAB"}">See full PDF</button><button class="ds2-5-button ds2-5-button--secondary js-swp-download-button" data-signup-modal="{"location":"download-pdf-button--work-card","attachmentId":49442107,"attachmentType":"pdf","workUrl":"https://www.academia.edu/5119057/Malignant_reversion_of_a_human_osteosarcoma_cell_line_Saos_2_by_inhibition_of_NF%CE%BAB"}"><span class="material-symbols-outlined" style="font-size: 20px" translate="no">download</span>Download PDF</button></div><div class="ds-signup-banner-trigger-container"><div class="ds-signup-banner-trigger ds-signup-banner-trigger-control"></div></div><div class="ds-signup-banner ds-signup-banner-control"><div id="ds-signup-banner-close-button"><button class="ds2-5-button ds2-5-button--secondary ds2-5-button--inverse"><span class="material-symbols-outlined" style="font-size: 20px" translate="no">close</span></button></div><div class="ds-signup-banner-ctas"><img src="//a.academia-assets.com/images/academia-logo-capital-white.svg" /><h4 class="ds2-5-heading-serif-sm">Sign up for access to the world's latest research</h4><button class="ds2-5-button ds2-5-button--inverse ds2-5-button--full-width js-swp-download-button" data-signup-modal="{"location":"signup-banner"}">Sign up for free<span class="material-symbols-outlined" style="font-size: 20px" translate="no">arrow_forward</span></button></div><div class="ds-signup-banner-divider"></div><div class="ds-signup-banner-reasons"><div class="ds-signup-banner-reasons-item"><span class="material-symbols-outlined" style="font-size: 24px" translate="no">check</span><span>Get notified about relevant papers</span></div><div class="ds-signup-banner-reasons-item"><span class="material-symbols-outlined" style="font-size: 24px" translate="no">check</span><span>Save papers to use in your research</span></div><div class="ds-signup-banner-reasons-item"><span class="material-symbols-outlined" style="font-size: 24px" translate="no">check</span><span>Join the discussion with peers</span></div><div class="ds-signup-banner-reasons-item"><span class="material-symbols-outlined" style="font-size: 24px" translate="no">check</span><span>Track your impact</span></div></div></div><script>(() => { // Set up signup banner show/hide behavior: // 1. 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We compared in vivo osteoinductivity of human osteosarcoma cell lines (Saos-2 vs. U-2 OS) in nude mice, and their in vitro expression of various osteogenic factors of protein level by quantitative immunocytochemistry and mRNA level by RT-PCR and/or in situ hybridization. Saos-2 cells, but not U-2 OS, were osteoinductive in vivo. Significantly higher expression (independent t-test, all p Ͻ 0.005) of osteogenic factors were observed in Saos-2 cells compared with U-2 OS, which included bone morphogenetic proteins (particularly BMPs-2, 3, 4, and 7), transforming growth factor-beta (TGF-␤), BMP receptor (BMPR)-1A, receptor-regulated Smads (R-Smads), Smads 1, 2, and 5, and common-mediator Smad (Co-Smad), Smad 4. In contrast, U-2 OS cells expressed higher levels of inhibitory Smad 6 (I-Smad) protein than Saos-2 cells (p Ͻ 0.001). These results suggest that a combination of osteogenic factors (BMPs, TGF-␤, BMPRs, and R/Co-Smads) against I-Smad may play important roles in the Saos-2 cell osteoinductivity. This may have a clinical implication in selecting key osteogenic factors for combined therapy for bone defect diseases. The characterized cell lines can be used as positive and negative controls for the assessments of both in vitro and in vivo bone formation capabilities of designed tissues or biomaterials.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Differential expression of osteogenic factors associated with osteoinductivity of human osteosarcoma cell lines","attachmentId":44139016,"attachmentType":"pdf","work_url":"https://www.academia.edu/14449593/Differential_expression_of_osteogenic_factors_associated_with_osteoinductivity_of_human_osteosarcoma_cell_lines","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/14449593/Differential_expression_of_osteogenic_factors_associated_with_osteoinductivity_of_human_osteosarcoma_cell_lines"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="1" data-entity-id="14824965" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/14824965/Novel_functions_for_NF%CE%BAB_inhibition_of_bone_formation">Novel functions for NFκB: inhibition of bone formation</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="33785487" href="https://uthsc.academia.edu/SusanKrum">Susan Krum</a></div><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Novel functions for NFκB: inhibition of bone formation","attachmentId":43872797,"attachmentType":"pdf","work_url":"https://www.academia.edu/14824965/Novel_functions_for_NF%CE%BAB_inhibition_of_bone_formation","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/14824965/Novel_functions_for_NF%CE%BAB_inhibition_of_bone_formation"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="2" data-entity-id="91440269" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/91440269/Bortezomib_inhibits_human_osteoclastogenesis">Bortezomib inhibits human osteoclastogenesis</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="246833419" href="https://independent.academia.edu/MarenMieth">Maren Mieth</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Leukemia, 2007</p><p class="ds-related-work--abstract ds2-5-body-sm">In multiple myeloma, the overexpression of receptor activator of nuclear factor kappa B (NF-jB) ligand (RANKL) leads to the induction of NF-jB and activator protein-1 (AP-1)-related osteoclast activation and enhanced bone resorption. The purpose of this study was to examine the molecular and functional effects of proteasome inhibition in RANKL-induced osteoclastogenesis. Furthermore, we aimed to compare the outcome of proteasome versus selective NF-jB inhibition using bortezomib (PS-341) and I-jB kinase inhibitor PS-1145. Primary human osteoclasts were derived from CD14 þ precursors in presence of RANKL and macrophage colony-stimulating factor (M-CSF). Both bortezomib and PS-1145 inhibited osteoclast differentiation in a dose-and time-dependent manner and furthermore, the bone resorption activity of osteoclasts. The mechanisms of action involved in early osteoclast differentiation were found to be related to the inhibition of p38 mitogenactivated protein kinase pathways, whereas the later phase of differentiation and activation occurred due to inhibition of p38, AP-1 and NF-jB activation. The AP-1 blockade contributed to significant reduction of osteoclastic vascular endothelial growth factor production. In conclusion, our data demonstrate that proteasomal inhibition should be considered as a novel therapeutic option of cancer-induced lytic bone disease.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Bortezomib inhibits human osteoclastogenesis","attachmentId":94727680,"attachmentType":"pdf","work_url":"https://www.academia.edu/91440269/Bortezomib_inhibits_human_osteoclastogenesis","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/91440269/Bortezomib_inhibits_human_osteoclastogenesis"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="3" data-entity-id="25173775" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/25173775/Selective_inhibition_of_NF_%CE%BAB_suppresses_bone_invasion_by_oral_squamous_cell_carcinoma_in_vivo">Selective inhibition of NF-κB suppresses bone invasion by oral squamous cell carcinoma in vivo</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="48475099" href="https://independent.academia.edu/TetsuTakahashi">Tetsu Takahashi</a></div><p class="ds-related-work--metadata ds2-5-body-xs">International Journal of Cancer, 2012</p><p class="ds-related-work--abstract ds2-5-body-sm">Nuclear factor-jB (NF-jB) is constitutively activated in many cancers, including oral squamous cell carcinoma (OSCC), and is involved in the invasive characteristics of OSCC, such as growth, antiapoptotic activity and protease production. However, the cellular mechanism underlying NF-jB's promotion of bone invasion by OSCC is unclear. Therefore, we investigated the role of NF-jB in bone invasion by OSCC in vivo. Immunohistochemical staining of OSCC invading bone in 10 patients indicated that the expression and nuclear translocation of p65, a main subunit of NF-jB, was increased in OSCC compared with normal squamous epithelial cells. An active form of p65 phosphorylated at serine 536 was present mainly in the nucleus in not only differentiated tumor cells but also tumor-associated stromal cells and bone-resorbing osteoclasts. We next injected mouse OSCC SCCVII cells into the masseter region of C 3 H/HeN mice. Mice were treated for 3 weeks with a selective NF-jB inhibitor, NBD peptide, which disrupts the association of NF-jB essential modulator (NEMO) with IjB kinases. NBD peptide treatment inhibited TNFa-induced and constitutive NF-jB activation in SCCVII cells in vitro and in vivo, respectively. Treatment with NBD peptide decreased zygoma and mandible destruction by SCCVII cells, reduced number of osteoclasts by inhibiting RANKL expression in osteoblastic cells and SCCVII cells, increased apoptosis and suppressed the proliferation of SCCVII cells. Taken together, our data clearly indicate that inhibition of NF-jB is useful for inhibiting bone invasion by OSCC.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Selective inhibition of NF-κB suppresses bone invasion by oral squamous cell carcinoma in vivo","attachmentId":45490040,"attachmentType":"pdf","work_url":"https://www.academia.edu/25173775/Selective_inhibition_of_NF_%CE%BAB_suppresses_bone_invasion_by_oral_squamous_cell_carcinoma_in_vivo","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/25173775/Selective_inhibition_of_NF_%CE%BAB_suppresses_bone_invasion_by_oral_squamous_cell_carcinoma_in_vivo"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="4" data-entity-id="121545143" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/121545143/Biology_and_pathogenesis_of_human_osteosarcoma_Review_">Biology and pathogenesis of human osteosarcoma (Review)</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="20947959" href="https://independent.academia.edu/ThalesFernandes3">Thales Fernandes</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Oncology Letters, 2019</p><p class="ds-related-work--abstract ds2-5-body-sm">Osteosarcoma (OS) is a bone tumor of mesenchymal origin, most frequently occurring during the rapid growth phase of long bones, and usually located in the epiphyseal growth plates of the femur or the tibia. Its most common feature is genome disorganization, aneuploidy with chromosomal alterations, deregulation of tumor suppressor genes and of the cell cycle, and an absence of DNA repair. This suggests the involvement of surveillance failures, DNA repair or apoptosis control during osteogenesis, allowing the survival of cells which have undergone alterations during differentiation. Epigenetic events, including DNA methylation, histone modifications, nucleosome remodeling and expression of non-coding RNAs have been identified as possible risk factors for the tumor. It has been reported that p53 target genes or those genes that have their activity modulated by p53, in addition to other tumor suppressor genes, are silenced in OS-derived cell lines by hypermethylation of their promoters. In osteogenesis, osteoblasts are formed from pluripotent mesenchymal cells, with potential for self-renewal, proliferation and differentiation into various cell types. This involves complex signaling pathways and multiple factors. Any disturbance in this process can cause deregulation of the differentiation and proliferation of these cells, leading to the malignant phenotype. Therefore, the origin of OS seems to be multifactorial, involving the deregulation of differentiation of mesenchymal cells and tumor suppressor genes, activation of oncogenes, epigenetic events and the production of cytokines. Contents 1. Introduction 2. Biology of human OS 3. Role of differentiation of mesenchymal stem cells 4. Role of DNA changes 5. Role of deregulating the expression of tumor suppressor genes 6. Regulation of oncogene expression 7. Role of epigenetic mechanisms 8. Role of non-coding RNAs 9. Role of cytokines 10. Conclusion</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Biology and pathogenesis of human osteosarcoma (Review)","attachmentId":116392373,"attachmentType":"pdf","work_url":"https://www.academia.edu/121545143/Biology_and_pathogenesis_of_human_osteosarcoma_Review_","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/121545143/Biology_and_pathogenesis_of_human_osteosarcoma_Review_"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="5" data-entity-id="46982047" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/46982047/Pathophysiology_and_Pharmacological_Targeting_of_Tumor_Induced_Bone_Disease_Current_Status_and_Emerging_Therapeutic_Interventions">Pathophysiology and Pharmacological Targeting of Tumor-Induced Bone Disease: Current Status and Emerging Therapeutic Interventions</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="32731489" href="https://upatras.academia.edu/ASymeonidis">A. Symeonidis</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Current Medicinal Chemistry, 2011</p><p class="ds-related-work--abstract ds2-5-body-sm">Solid tumors such as breast, prostate, thyroid, lung and renal cell cancer exhibit significant osteotropism and often metastasize in the skeleton . Bone metastasis is a major cause of morbidity and mortality of several carcinomas. The tendency of certain solid tumors to colonize bone tissue is currently explained by the concept of organ-specific metastasis, introduced by the -seed and soil‖ hypothesis, initially proposed by Dr. Steven Paget, more than one hundred years ago . Dr. Paget proposed that a receptive microenvironment (soil) is present in certain organs, and this is the prerequisite for circulating cancer cells (seeds) to colonize it and develop metastases. This microenvironment offers the fertile ‗‗soil'' where neoplastic cells can reside, grow and develop. Bone metastasis usually occurs during the late stages of cancer progression, and involves a complex multistep process, which involves alterations in the structure and/or expression of specific genes, resulting in the acquisition of an advanced malignant phenotype by the cell . Cancer cells must express the appropriate phenotype to successfully leave the primary tumor, grow in the adjacent mesenchyme, survive in the blood-stream, attach to the endothelial cells, transverse them, and finally invade and proliferate at secondary sites. Metastatic bone disease is classified as either osteolytic or osteblastic. Osteolytic-type metastases are more common and are characterized by significant bone disruption due to enhanced osteoclastic activity. In contrast, osteoblastic metastases are less common, and are characterized by over-production of osseous tissue by activated osteoblasts. These two types of bone destruction represent the two extremes of a continuum of metastasis-associated bone pathology since in the majority of the cases both, the osteolytic and the osteoblastic component co-exist. Metastases of breast and lung 4 cancer are predominantly osteolytic. On the other hand, prostate cancer typically develops osteoblastic metastases . Bone disease is also developed in multiple myeloma, a B-cell neoplasm, characterized by expansion within the bone marrow of a malignant plasma cell clone, which leads to the formation of typical osteolytic lesions . Bone disease is often associated with various skeletal events such as bone pain, pathological fractures, hypercalcemia, various nerve compression syndromes, paralysis and bone marrow aplasia . Occasionlly, bone destruction can also be observed in other hematological malignancies of lymphoid (non-Hodgkin's lymphoma, acute lymphoblastic leukemia, chronic lympocytic leukemia) and of nonlymphoid origin (acute myelogenous leukemia, Langerhans-and non-Langerhans cell's histiocytosis, etc.).</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Pathophysiology and Pharmacological Targeting of Tumor-Induced Bone Disease: Current Status and Emerging Therapeutic Interventions","attachmentId":66320714,"attachmentType":"pdf","work_url":"https://www.academia.edu/46982047/Pathophysiology_and_Pharmacological_Targeting_of_Tumor_Induced_Bone_Disease_Current_Status_and_Emerging_Therapeutic_Interventions","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/46982047/Pathophysiology_and_Pharmacological_Targeting_of_Tumor_Induced_Bone_Disease_Current_Status_and_Emerging_Therapeutic_Interventions"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="6" data-entity-id="120601426" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/120601426/NF_%CE%BAB_in_breast_cancer_cells_promotes_osteolytic_bone_metastasis_by_inducing_osteoclastogenesis_via_GM_CSF">NF-κB in breast cancer cells promotes osteolytic bone metastasis by inducing osteoclastogenesis via GM-CSF</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="44162203" href="https://independent.academia.edu/ShaoqiongChen">Shaoqiong Chen</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Nature Medicine, 2006</p><p class="ds-related-work--abstract ds2-5-body-sm">Advanced breast cancers frequently metastasize to bone, resulting in osteolytic lesions, yet the underlying mechanisms are poorly understood. Here we report that nuclear factor-jB (NF-jB) plays a crucial role in the osteolytic bone metastasis of breast cancer by stimulating osteoclastogenesis. Using an in vivo bone metastasis model, we found that constitutive NF-jB activity in breast cancer cells is crucial for the bone resorption characteristic of osteolytic bone metastasis. We identified the gene encoding granulocyte macrophage-colony stimulating factor (GM-CSF) as a key target of NF-jB and found that it mediates osteolytic bone metastasis of breast cancer by stimulating osteoclast development. Moreover, we observed that the expression of GM-CSF correlated with NF-jB activation in bone-metastatic tumor tissues from individuals with breast cancer. These results uncover a new and specific role of NF-jB in osteolytic bone metastasis through GM-CSF induction, suggesting that NF-jB is a potential target for the treatment of breast cancer and the prevention of skeletal metastasis. Breast cancer is the most common cancer affecting women in the United States and other western countries. In individuals with breast cancer, the frequency of bone metastasis is much higher than that of lung and liver metastases . In contrast to prostate cancer, which forms osteoblastic lesions, skeletal metastasis of breast cancer typically leads to osteolysis, which is often accompanied by severe pain, pathological fracture and hypercalcemia . Although the molecular mechanism underlying the preferential metastasis of breast cancer to bone is yet to be elucidated, it is believed that osteoclasts activated by breast cancer cells mediate osteolysis. Osteoclasts have an initiating and integral role in stimulating bone-metastatic tumor growth in the marrow cavity. Whereas bone microenvironments allow circulating breast cancer cells to preferentially arrest, colonize and survive, boneseeking cancer cells may have an intrinsic ability to promote osteoclast formation and activation . In bone metastasis of breast cancer, there is a vicious cycle wherein bone-residing tumor cells stimulate osteoclast-mediated bone destruction, and bone-stored growth factors released from resorbed bone promote tumor growth. Therefore, the recruitment, formation and activation of osteoclasts mediated by breast cancer cells are crucial for initiating the vicious cycle of osteolytic bone metastasis of breast cancer . Genes associated with tumor invasion and metastasis, including those encoding matrix metalloproteinases and interleukin-8 (IL-8), are regulated by NF-kB, suggesting that NF-kB plays a crucial role in metastasis in general . It is not surprising that blocking NF-kB activity suppresses tumor growth and metastasis in vitro and in vivo.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"NF-κB in breast cancer cells promotes osteolytic bone metastasis by inducing osteoclastogenesis via GM-CSF","attachmentId":115981806,"attachmentType":"pdf","work_url":"https://www.academia.edu/120601426/NF_%CE%BAB_in_breast_cancer_cells_promotes_osteolytic_bone_metastasis_by_inducing_osteoclastogenesis_via_GM_CSF","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/120601426/NF_%CE%BAB_in_breast_cancer_cells_promotes_osteolytic_bone_metastasis_by_inducing_osteoclastogenesis_via_GM_CSF"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="7" data-entity-id="27353576" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/27353576/Inhibition_of_the_classical_NF_%CE%BAB_pathway_prevents_osteoclast_bone_resorbing_activity">Inhibition of the classical NF-κB pathway prevents osteoclast bone-resorbing activity</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="51469645" href="https://independent.academia.edu/NeilAlles">Neil Alles</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Journal of Bone and Mineral Metabolism, 2009</p><p class="ds-related-work--abstract ds2-5-body-sm">The classical NF-jB pathway plays an important role in osteoclast formation and differentiation; however, the role of NF-jB in osteoclast bone-resorbing activity is not well understood. To elucidate whether NF-jB is important for osteoclast bone-resorbing activity, we used a selective peptide inhibitor of the classical NF-jB pathway named the NBD peptide. Osteoclasts were generated using bone marrow macrophages in the presence of M-CSF and RANKL. The NBD peptide dose-dependently blocked the bone-resorbing activity of osteoclasts by reducing area, volume (p \ 0.001) and depths (p \ 0.05) of pits. The reduced resorption by the peptide was due to reduced osteoclast bone-resorbing activity, but not reduced differentiation as the number of osteoclasts was similar in all groups. The peptide inhibited bone resorption by reducing TRAP activity, disrupting actin rings and preventing osteoclast migration. Gene expressions of a panel of bone resorption markers were significantly reduced. The NBD peptide dose-dependently reduced the RANKLinduced c-Src kinase activity, which is important for actin ring formation and osteoclast bone resorption. Therefore, these data suggest that the classical NF-jB pathway plays a pivotal role in osteoclast bone-resorbing activity.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Inhibition of the classical NF-κB pathway prevents osteoclast bone-resorbing activity","attachmentId":47608583,"attachmentType":"pdf","work_url":"https://www.academia.edu/27353576/Inhibition_of_the_classical_NF_%CE%BAB_pathway_prevents_osteoclast_bone_resorbing_activity","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/27353576/Inhibition_of_the_classical_NF_%CE%BAB_pathway_prevents_osteoclast_bone_resorbing_activity"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="8" data-entity-id="21824404" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/21824404/In_vitro_transformation_of_osteoblasts_Putative_formation_of_osteosarcoma_in_vitro">In vitro transformation of osteoblasts: Putative formation of osteosarcoma in vitro</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="43068296" href="https://independent.academia.edu/CBirek">C. Birek</a><span>, </span><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="43047996" href="https://independent.academia.edu/MockDavid">David Mock</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Bone, 1987</p><p class="ds-related-work--abstract ds2-5-body-sm">The study of bone cancer has been difficult in part due to a lack of appropriate in vitro osteosarcoma model systems. The development of such systems is essential if a clearer understanding of the biology of and mechanisms behind the formation and progression of bone cancers is to be obtained. We report here the development of an in vitro model system which demonstrates important characteristics generally associated with osteosarcoma.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"In vitro transformation of osteoblasts: Putative formation of osteosarcoma in vitro","attachmentId":42577176,"attachmentType":"pdf","work_url":"https://www.academia.edu/21824404/In_vitro_transformation_of_osteoblasts_Putative_formation_of_osteosarcoma_in_vitro","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/21824404/In_vitro_transformation_of_osteoblasts_Putative_formation_of_osteosarcoma_in_vitro"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="9" data-entity-id="18325507" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/18325507/Bone_deposition_bone_resorption_and_osteosarcoma">Bone deposition, bone resorption, and osteosarcoma</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="38317850" href="https://einstein.academia.edu/ReynaldoJesusGarciaFilho">Reynaldo Jesus Garcia Filho</a><span>, </span><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="43577024" href="https://independent.academia.edu/CarlaRenataPachecoDonatoMacedo">Carla Renata Pacheco Donato Macedo</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Journal of Orthopaedic Research, 2010</p><p class="ds-related-work--abstract ds2-5-body-sm">Bone deposition and bone resorption are ongoing dynamic processes, constituting bone remodeling. Some bone tumors, such as osteosarcoma (OS), stimulate focal bone deposition. OS is the most common primary bone tumor in children and young adults. A complex network of genes regulates bone remodeling and alterations in its expression levels can influence the genesis and progression of bone diseases, including OS. We hypothesized that the expression profiles of bone remodeling regulator genes would be correlated with OS biology and clinical features. We used real-time PCR to evaluate the mRNA levels of the tartrate-resistant acid phosphatase (ACP5), colony stimulating factor-1 (CSF1R), bone morphogenetic protein 7 (BMP7), collagen, type XI, alpha 2 (COL11A2), and protein tyrosine phosphatases zeta 1 (PTPRZ1) genes, in 30 OS tumor samples and correlated with clinical and histological data. All genes analyzed, except CSF1R, were differentially expressed when compared with normal bone expression profiles. In our results, OS patients with high levels of COL11A2 mRNA showed worse overall (p ¼ 0.041) and event free survival (p ¼ 0.037). Also, a trend for better overall survival was observed in patients with samples showing higher expression of BMP7 (p ¼ 0.067). COL11A2 overexpression and BMP7 underexpression could collaborate to OS tumor growth, through its central role in bone remodeling process. ß</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Bone deposition, bone resorption, and osteosarcoma","attachmentId":39995989,"attachmentType":"pdf","work_url":"https://www.academia.edu/18325507/Bone_deposition_bone_resorption_and_osteosarcoma","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/18325507/Bone_deposition_bone_resorption_and_osteosarcoma"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div></div></div><div class="ds-sticky-ctas--wrapper js-loswp-sticky-ctas hidden"><div class="ds-sticky-ctas--grid-container"><div class="ds-sticky-ctas--container"><button class="ds2-5-button js-swp-download-button" data-signup-modal="{"location":"continue-reading-button--sticky-ctas","attachmentId":49442107,"attachmentType":"pdf","workUrl":null}">See full PDF</button><button class="ds2-5-button ds2-5-button--secondary js-swp-download-button" data-signup-modal="{"location":"download-pdf-button--sticky-ctas","attachmentId":49442107,"attachmentType":"pdf","workUrl":null}"><span class="material-symbols-outlined" style="font-size: 20px" translate="no">download</span>Download PDF</button></div></div></div><div class="ds-below-fold--grid-container"><div class="ds-work--container js-loswp-embedded-document"><div class="attachment_preview" data-attachment="Attachment_49442107" style="display: none"><div class="js-scribd-document-container"><div class="scribd--document-loading js-scribd-document-loader" style="display: block;"><img alt="Loading..." src="//a.academia-assets.com/images/loaders/paper-load.gif" /><p>Loading Preview</p></div></div><div style="text-align: center;"><div class="scribd--no-preview-alert js-preview-unavailable"><p>Sorry, preview is currently unavailable. You can download the paper by clicking the button above.</p></div></div></div></div><div class="ds-sidebar--container js-work-sidebar"><div class="ds-related-content--container"><h2 class="ds-related-content--heading">Related papers</h2><div class="ds-related-work--container js-related-work-sidebar-card" data-collection-position="0" data-entity-id="99168509" data-sort-order="default"><a class="ds-related-work--title js-related-work-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/99168509/Pharmacological_evidence_for_the_bone_autonomous_contribution_of_the_NF%CE%BAB_%CE%B2_catenin_axis_to_breast_cancer_related_osteolysis">Pharmacological evidence for the bone-autonomous contribution of the NFκB/β-catenin axis to breast cancer related osteolysis</a><div class="ds-related-work--metadata"><a class="js-related-work-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="235518847" href="https://independent.academia.edu/silviamarino28">silvia 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