Abstract
Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder whose most debilitating pathology is progressive and cumulative heterotopic ossification (HO) of skeletal muscles, ligaments, tendons, and fascia. FOP is caused by amino acid-altering mutations in ACVR1, a type I BMP receptor. The mutations occur in the region encoding the intracellular domain of ACVR1 and bestow FOP-mutant ACVR1 with the neofuction of recognizing Activin A as an agonistic ligand. (In contrast, Activin A antagonizes BMP signaling from wild type ACVR1.) This neofuction is required for HO in FOP as inhibition of Activin A stops the initiation and progression of heterotopic bone lesions in FOP. These results unequivocally demonstrated that HO in FOP is dependent on activation of FOP-mutant ACVR1 by ligand and set the stage to explore ACVR1-blocking antibodies as an additional potential therapeutic for FOP. Surprisingly, ACVR1 antibodies stimulate – rather than inhibit – HO and induce Smad1/5/8 phosphorylation of FOP-mutant ACVR1. This property is restricted to FOP-mutant ACVR1, as signaling by wild type ACVR1 is inhibited by these antibodies, as is trauma-induced HO. These results uncover yet an additional novel property of FOP-mutant ACVR1 and indicate that anti-ACVR1 antibodies should not be considered as a therapeutic strategy for FOP.
Competing Interest Statement
The authors have declared no competing interest.