{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T01:33:53Z","timestamp":1793151233473,"version":"4.5.0"},"reference-count":28,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,4,25]],"date-time":"2025-04-25T00:00:00Z","timestamp":1745539200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012669","name":"Natural Science Foundation Project of Chongqing, Chongqing Science and Technology Commission","doi-asserted-by":"publisher","award":["CSTB2023NSCQ-LZX0049 CSTB2022NSCQ-MSX0110"],"award-info":[{"award-number":["CSTB2023NSCQ-LZX0049 CSTB2022NSCQ-MSX0110"]}],"id":[{"id":"10.13039\/501100012669","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>Bone fragility in type 2 diabetes mellitus (T2DM) is often characterized by impaired bone quality, despite normal or increased bone mineral density. Serum sclerostin levels are elevated in diabetes, yet its role in bone fragility is not fully understood. Sclerostin (SOST) is a Wnt signaling inhibitor primarily secreted by osteocytes, regulating bone formation and homeostasis. Sclerostin inhibits Wnt signaling, suppressing osteoblast differentiation and activity, which limits bone formation. However, the localized effects of sclerostin within the osteocyte lacunar-canalicular system (LCS) and its contribution to bone fragility in T2DM remain unclear. In this study, we investigated the role of elevated sclerostin in bone fragility using the <jats:italic>db\/db<\/jats:italic> mice. We found that <jats:italic>db\/db<\/jats:italic> mice exhibited significant osteoporosis, increased bone fragility, and structural damage to the LCS. Sclerostin expression was elevated, and its accumulation within the cortical bone LCS correlated with increased expression of matrix-degrading enzymes, including Cathepsin K (CTSK) and matrix metalloproteinase 13 (MMP-13). Further <jats:italic>in vitro<\/jats:italic> experiments with recombinant sclerostin confirmed the upregulation of these enzymes, suggesting that sclerostin\u2019s local effects within the LCS contribute to matrix degradation. These preliminary findings indicate that localized sclerostin accumulation in LCS is associated with cortical bone microstructural alterations and fragility in <jats:italic>db\/db<\/jats:italic> male mice. This study highlights the potential of targeting sclerostin\u2019s local effects within the LCS as a therapeutic strategy to prevent bone deterioration in diabetes.<\/jats:p>","DOI":"10.3389\/fcell.2025.1562764","type":"journal-article","created":{"date-parts":[[2025,4,25]],"date-time":"2025-04-25T05:26:15Z","timestamp":1745558775000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["Localized sclerostin accumulation in osteocyte lacunar-canalicular system is associated with cortical bone microstructural alterations and bone fragility in db\/db male mice"],"prefix":"10.3389","volume":"13","author":[{"given":"Xingfan","family":"Wu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanli","family":"Ai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutao","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,4,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"366","DOI":"10.1007\/s11914-014-0213-4","article-title":"Biological regulation of bone quality","volume":"12","author":"Alliston","year":"2014","journal-title":"Curr. 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