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

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder in which a recurrent ACVR1 (R206H) mutation drives progressive heterotopic ossification (HO). Although hypersensitive BMP signaling is well established, the mechanisms by which this mutation stabilizes a pro-osteogenic cell state remain unclear. Here, we integrated super-resolution stochastic optical reconstruction microscopy (STORM), transposase-accessible chromatin with sequencing (ATAC-Seq), and RNA sequencing (RNA-Seq) to determine how Acvr1R206H remodels chromatin to influence lineage commitment. Mutant mouse embryonic fibroblasts exhibited globally decondensed chromatin and enhanced accessibility at developmental and osteogenic loci, accompanied by transcriptional programs enriched for ossification, extracellular matrix organization, and cell adhesion. Upon BMP stimulation, Acvr1R206H/+ cells exhibited exaggerated chromatin remodeling, revealing markedly heightened ligand sensitivity. Notably, pharmacological inhibition of Rho/ROCK or BMP-SMAD signaling restored chromatin condensation, demonstrating that these chromatin alterations are dynamic and reversible. Together, these findings show that Acvr1R206H establishes a pro-osteogenic chromatin landscape through convergent Rho/ROCK-dependent mechanotransduction and BMP-dependent pathways, revealing potential therapeutic opportunities to prevent pathological bone formation in FOP.