Hyperactive BMP and Mechanosignaling Remodel Chromatin to Drive Aberrant Osteogenesis in FOP

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder in which a mutation in ACVR1/ALK2 drives progressive heterotopic ossification. However, how this mutation enforces a persistent pro-osteogenic state is unclear. Here, we show that the <i>Acvr1 ^R206H</i> mutation remodels chromatin architecture and accessibility through hyperactive BMP-SMAD and Rho/ROCK signaling, activating transcription factor networks that drive osteochondrogenic gene expression. These chromatin changes are dynamic and reversible with targeted pathway inhibition, revealing therapeutic potential to restore mesenchymal cell plasticity and prevent pathological bone formation.