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Here we identify osteomodulin (OMD), a matrix-associated osteoblast-derived protein that is reduced in the bone tissue and serum of postmenopausal patients with osteoporosis. Inducible global or osteoblast-specific\n                    <jats:italic>Omd<\/jats:italic>\n                    deletion exacerbates bone loss and increases osteoclast activity, whereas osteoclast precursor-specific deletion produces no overt skeletal phenotype. Mechanistically, OMD engages integrin \u03b28 on osteoclast precursors, suppresses RhoA activity and enhances YAP phosphorylation, thereby reducing YAP\/TEAD occupancy at the ribonucleotide reductase M2 (RRM2) promoter and repressing\n                    <jats:italic>Rrm2<\/jats:italic>\n                    transcription. Consistent with RRM2\u2019s role in maintaining the dNTP pools required for mitochondrial DNA replication, OMD decreases mtDNA copy number and the abundance of electron transport chain proteins, leading to reduced mitochondrial respiration and ATP production, with only limited glycolytic compensation. Finally, recombinant OMD supplementation or pharmacologic RRM2 inhibition mitigates ovariectomy and lipopolysaccharide-induced bone loss. Together, our findings identify an OMD-integrin \u03b28-RhoA-YAP\/TEAD-RRM2 axis that links extracellular matrix signaling to mitochondrial respiration and mitochondrial ATP production during osteoclastogenesis.\n                  <\/jats:p>","DOI":"10.1038\/s12276-026-01682-7","type":"journal-article","created":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T01:48:23Z","timestamp":1773280103000},"page":"879-897","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Osteoblast-derived osteomodulin restrains osteoclastogenesis via ITGB8\/RRM2-mediated reduction of mitochondrial respiration and mitochondrial ATP production"],"prefix":"10.1038","volume":"58","author":[{"given":"Xiaowen","family":"Jiang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiduo","family":"Hou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengxin","family":"Dai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruijie","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erman","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanyi","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianbin","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mo","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xun","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxiao","family":"Ji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyong","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanbin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaorong","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohua","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weixu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,12]]},"reference":[{"key":"1682_CR1","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1038\/s41574-020-0339-7","volume":"16","author":"IR Reid","year":"2020","unstructured":"Reid, I. 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