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 Acvr1 R206H expression. Intermuscular fascial layers were the primary sites of lesional growth when HO was exacerbated by genetic, pharmacological, or physical means. In contrast to control mice, fascial injury in FOP mice caused pronounced destruction of the muscle subjacent to the injured fascia. Further, areas of muscle degeneration did not undergo a productive regenerative response. Unlike most models of impaired regeneration, adipocyte accumulations were not observed in areas of muscle degeneration, which were destined for pathological bone formation. These data point to the primary role of fascia in HO initiation and growth, and indicate that Acvr1 R206H -expressing FAPs directly or indirectly create an abnormal tissue environment that destabilizes muscle tissue and is incompatible with muscle regeneration. The advantages of this new model of injury-induced HO for understanding early events in FOP pathogenesis are discussed.