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Osteomodulin (OMD) is recognized for its essential role in bone morphogenetic protein 2 (BMP2)\u2010driven osteogenic differentiation. However, its role in osteoporosis, has not been systematically investigated. Here, we carried out omics studies on osteoporotic data obtained from the NCBI database and showed that OMD is mainly expressed in osteoprogenitor cells and that OMD expression levels are down\u2010regulated under bone loss conditions. OMD osteoblast\u2010specific conditional knockout mice (\n                    <jats:italic>OSTEOCALCIN\u2010Cre (OC\u2010Cre)<\/jats:italic>\n                    ;\n                    <jats:italic>Omd<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>flox\/flox<\/jats:italic>\n                    <\/jats:sup>\n                    ) were generated by CRISPR and an ovariectomy (OVX)\u2010induced model of osteoporosis was constructed in mice. Micro\u2010CT of OVX mice indicated that the trabecular bone volume fraction (BV\/TV) was significantly decreased in\n                    <jats:italic>OC\u2010Cre<\/jats:italic>\n                    ;\n                    <jats:italic>Omd<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>flox\/flox<\/jats:italic>\n                    <\/jats:sup>\n                    mice. Tartrate resistant acid phosphatase (TRAP) staining showed an increase in the number of osteoclasts in the femurs of\n                    <jats:italic>OC\u2010Cre<\/jats:italic>\n                    ;\n                    <jats:italic>Omd<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>flox\/flox<\/jats:italic>\n                    <\/jats:sup>\n                    mice. TRAP and immunofluorescence staining indicated that OMD treatment inhibited osteoclast differentiation of bone marrow\u2010derived macrophages (BMDMs) in\u00a0vitro. RNA sequencing showed that OMD treatment significantly affected osteoclast differentiation signaling pathways, while western blot analysis revealed that OMD treatment decreased the phosphorylation of JNK, ERK, p38, AKT, and I\u03baB\u03b1 in BMDMs. Molecular docking analysis predicted that OMD binds to receptor activator of nuclear factor kappa beta ligand (RANKL), which was verified by co\u2010immunoprecipitation. Further molecular docking simulations indicated that OMD shares overlapping binding regions on RANKL with osteoprotegerin and RANK. Together, our findings indicate that OMD deficiency exacerbates bone loss in osteoporosis. Furthermore, OMD may impede osteoclastic differentiation in BMDMs by binding to RANKL.\n                  <\/jats:p>","DOI":"10.1096\/fj.202600222rr","type":"journal-article","created":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T08:07:53Z","timestamp":1779782873000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Osteoblast\u2010Derived Osteomodulin Suppresses Bone Loss in Osteoporosis by Inhibiting Osteoclastogenesis"],"prefix":"10.1096","volume":"40","author":[{"given":"Meiling","family":"Jing","sequence":"first","affiliation":[{"name":"Department of Endodontics Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine  Shanghai China"},{"name":"College of Stomatology Shanghai Jiao Tong University  Shanghai China"},{"name":"National Clinical Research Center for Oral Diseases, National Center for Stomatology Shanghai Key Laboratory of Stomatology  Shanghai 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