Osteoblast-derived osteomodulin restrains osteoclastogenesis via ITGB8/RRM2-mediated reduction of mitochondrial respiration and mitochondrial ATP production.

Osteoporosis is driven in part by excessive osteoclast-mediated bone resorption, yet osteoblast-derived extracellular cues that restrain osteoclast bioenergetics remain incompletely defined. 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 Omd deletion exacerbates bone loss and increases osteoclast activity, whereas osteoclast precursor-specific deletion produces no overt skeletal phenotype. Mechanistically, OMD engages integrin β8 on osteoclast precursors, suppresses RhoA activity and enhances YAP phosphorylation, thereby reducing YAP/TEAD occupancy at the ribonucleotide reductase M2 (RRM2) promoter and repressing Rrm2 transcription. Consistent with RRM2's 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 β8-RhoA-YAP/TEAD-RRM2 axis that links extracellular matrix signaling to mitochondrial respiration and mitochondrial ATP production during osteoclastogenesis.