USP24-dependent STAT2 stabilization mediates physiologic and pathologic bone formation

Osteoblast development must be precisely regulated, as insufficient bone formation results in low bone mass and skeletal fragility, whereas excessive osteogenesis drives heterotopic ossification (HO), the ectopic formation of bone in soft tissues. Here, we identify the deubiquitinating enzyme ubiquitin-specific peptidase 24 (USP24) as a key regulator of both physiological and pathological ossification. USP24 is highly expressed in skeletal tissues, where it promotes osteoblast development by stabilizing STAT2 through deubiquitination. Loss of USP24 reduces osteoblast differentiation and bone formation, an effect mirrored by STAT2 deficiency. Beyond physiologic bone, USP24 and STAT2 are also strongly expressed in heterotopic bones from patients with HO. In a fibrodysplasia ossificans progressiva (FOP) mouse model, recombinant adeno-associated virus (rAAV)-mediated silencing of Usp24 markedly diminished HO pathogenesis and reduced STAT2 protein levels in HO lesions. Consistently, USP24 deficiency attenuated activin A-induced bone morphogenetic protein (BMP) signaling and osteogenesis, with comparable effects observed upon Stat2 silencing. Together, these findings uncover a previously unrecognized role for USP24-STAT2 signaling in osteoblast differentiation and HO, highlighting bone-targeted USP24-STAT2 inhibition as a potential therapeutic strategy for pathologic bone formation.