IGSF10 regulates osteogenesis and osteoclastogenesis via a noncanonical EGFR-STAT1 signaling axis to promote skeletal regeneration.

Bone remodeling requires precise coordination between osteoblast-mediated bone formation and osteoclast-driven resorption. However, directly targetable and therapeutically actionable mediators that can coordinately modulate both processes during regeneration remain relatively limited. Here, we identify immunoglobulin superfamily member 10 (IGSF10) as a dual-function modulator of bone remodeling. Igsf10-deficient mice exhibit reduced bone mass, elevated osteoclast activity, and impaired osteogenesis. Recombinant IGSF10 protein restores osteogenic capacity and suppresses osteoclastogenesis in knockout cells, while exerting pro-osteogenic and anti-resorptive effects in wild-type mesenchymal and monocyte-derived cultures. Mechanistically, IGSF10 activates a noncanonical EGFR-STAT1 signaling pathway, distinct from BMP2-Smad signaling. Co-immunoprecipitation and molecular docking confirm IGSF10-EGFR interaction, and blockade of EGFR abrogates IGSF10-induced osteogenesis and its inhibitory effects on osteoclastogenesis. In vivo, IGSF10 promotes bone regeneration in both calvarial and periodontal defect models and exhibits synergy with subtherapeutic BMP2. These findings position IGSF10 as a previously unrecognized dual-acting regulator that coordinates bone formation and resorption in a context-dependent manner, with potential therapeutic value for craniofacial and skeletal regeneration.