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Understanding the cellular metabolism of osteoclasts (OCs) is key to developing new treatments for osteoporosis, a disease that affects over 200 million women worldwide per annum. We found that human OC differentiation from peripheral blood mononuclear cells derived from 8 female patients is featured with a distinct gene expression profile of mitochondrial biogenesis. Elevated mitochondrial membrane potential (MMP, \u0394\u03c8m) was also observed in receptor activator of NF-\u03baB ligand (RANKL)-induced OCs. Interestingly, the gene pathways of heme synthesis and metabolism were activated upon RANKL stimulation, featured by transcriptomic profiling in murine cells at a single-cell resolution, which revealed a stepwise expression pattern of heme-related genes. The real-world human data also divulges potential links between heme-related genes and bone mineral density. Heme is known to have a role in the formation of functional mitochondrial complexes that regulate MMP. Disruption of heme biosynthesis via genetically silencing Ferrochelatase or a selective inhibitor, N-methyl Protoporphyrin IX (NMPP), demonstrated potent inhibition of OC differentiation, with a dose-dependent effect observed in NMPP treatment and a substantial efficacy even at a single dose. In vivo study further showed the protective effect of NMPP on ovariectomy-induced bone loss in female mice. Collectively, we found that RANKL-mediated signaling regulated mitochondrial formation and heme metabolism to synergistically support osteoclastogenesis. Inhibition of heme synthesis impaired OC formation and reversed excessive bone loss, representing a new therapeutic target for metabolic skeletal disorders.<\/jats:p>","DOI":"10.1093\/jbmr\/zjaf040","type":"journal-article","created":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T23:02:22Z","timestamp":1741820542000},"page":"639-655","source":"Crossref","is-referenced-by-count":15,"title":["Heme metabolism mediates RANKL-induced osteoclastogenesis via mitochondrial oxidative phosphorylation"],"prefix":"10.1093","volume":"40","author":[{"given":"Heng","family":"Qiu","sequence":"first","affiliation":[{"name":"School of Biomedical Sciences, University of Western Australia , Crawley, WA, 6009 ,","place":["Australia"]},{"name":"Department of Chemistry, The University of Hong Kong , Hong Kong SAR, 999077 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiming","family":"Jin","sequence":"additional","affiliation":[{"name":"School of Biomedical 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Endocrinology & Diabetes, Sir Charles Gairdner Hospital , Nedlands, WA, 6009 ,","place":["Australia"]},{"name":"Department of Endocrinology & Diabetes, Medical School, The University of Western Australia , Crawley, WA, 6009 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, University of Western Australia , Crawley, WA, 6009 ,","place":["Australia"]},{"name":"School of Molecular Sciences, The University of Western Australia , Crawley, WA, 6009 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronghe","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, First People's Hospital of Nanning, Fifth Affiliated Hospital of Guangxi Medical University , Nanning, 530022 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