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However, the detailed functions of osteocyte subsets in osteoporosis have remained obscure. In this study, it is aimed to investigate the impact of osteocyte subset heterogeneity on the pathological process of osteoporosis and new potential molecular mechanisms. Six osteocyte subsets are identified in mouse bones by single\u2010cell sequencing. Among them, the epidermal growth factor receptor (Egfr)+ interleukin\u20101 receptor type I (Il1r1)+ Semaphorin 5a (Sema5a)+osteocyte subpopulation (bone homeostasis regulatory osteocytes, BHR\u2010Ocys) played a key role in the maintenance of bone homeostasis by regulating osteoblasts and osteoclasts. The data confirm that the increased proportion of BHR\u2010Ocys contributes to bone loss in the postmenopausal osteoporotic mice. Mechanistically, Sema5a derived from BHR\u2010Ocys binds to the osteoclast receptor protein Plexin A1 (Plxna1), thereby activating the phosphatidylinositol\u20103 kinase\/protein kinase B\/myelocytomatosis oncogen (PI3K\/AKT\/Myc) signaling pathway, leading to active osteoclast\u2010mediated bone resorption. In conclusion, BHR\u2010Ocys is a key cell subpopulation in the regulation of bone homeostasis. The Sema5a\u2010Plxna1 axis is an important mechanism for BHR\u2010Ocys to regulate osteoclast differentiation. The study provides new insights into the role and mechanism of osteocytes in the regulation of bone homeostasis and identifies new targets for the prevention and treatment of osteoporosis.<\/jats:p>","DOI":"10.1002\/advs.202513427","type":"journal-article","created":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T09:42:17Z","timestamp":1763458937000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Identification and Mechanisms of Osteocyte Subsets Involved in the Pathological Progression of Osteoporosis"],"prefix":"10.1002","volume":"13","author":[{"given":"Zengxin","family":"Jiang","sequence":"first","affiliation":[{"name":"Department of Orthopaedics Shanghai Jiaotong University Affiliated Sixth People's Hospital  No. 600 Yishan Road Shanghai 200233 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Biyu","family":"Rui","sequence":"additional","affiliation":[{"name":"Department of 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