The role of muscle fascia in heterotopic ossification and maintenance of skeletal muscle integrity in fibrodysplasia ossificans progressiva.

The rare genetic disorder fibrodysplasia ossificans progressiva (FOP) is characterized by progressive heterotopic ossification (HO) of skeletal muscles and associated soft tissues. FOP is caused by a gain-of-function mutation in the type l BMP receptor ACVR1 (ALK2) that renders the receptor inappropriately responsive to activin ligands. HO is associated with muscle destruction and compromised muscle regeneration, although little is known of the mechanistic relationship between these pathophysiological disease manifestations. In mouse FOP models, HO is experimentally induced by direct injury to muscle using chemical or mechanical means, thereby obscuring the relationship between HO formation and muscle destruction. We show that direct muscle injury is not required for induction of a robust HO response. Rather, a small incision in the fascia superior to the tibialis anterior muscle was sufficient to induce HO when fibro-adipogenic progenitors (FAPs) were targeted for