Fibrodysplasia ossificans progressiva is a rare autosomal-dominant genetic disorder. Approximately 97% of cases are associated with the Arg206His mutation in the intracellular domain of ACVR1, the receptor for bone morphogenetic protein type I. Clinically, this mutation is characterized by conversion of soft tissue, including skeletal muscle, fascia tendons and ligaments, into bone. This process, termed heterotopic ossification, is debilitating; ultimately bones fuse together, causing immobility and asphyxiation.

Previous attempts to create a mouse model of this disease were hampered by perinatal lethality. To assess whether expression of mutant ACVR1 is sufficient to drive heterotopic ossification in vivo, Aris N. Economides and his colleagues at Regeneron Pharmaceuticals (Tarrytown, NY) generated a conditional-on knock-in model in which adult mice conditionally and endogenously express mutant ACVR1R206H after being injected with tamoxifen (Sci. Transl. Med. 7, 303ra137; 2015). Following induction of the transgene, mice develop progressive heterotopic ossification in the sternum, vertebrae, hip joint and hindlimb. The researchers then administered soluble mimics of the receptor to mice to assess whether the disease process requires a ligand to activate the receptor. These mimics mop up any endogenous ligands and inhibit them from binding to receptors, and administration successfully inhibited conversion of soft tissue to bone.

One such ligand, activin A, acts as an antagonist of wild-type ACVR1 and inhibits binding of other activating ligands like bone morphogenetic protein-2. However, in the knock-in model with mutant ACVR1, activin A has the opposite effect of promoting aberrant bone formation and ossification. In a press release, Economides noted that “gaining insight into the activin A-related mechanism is a tremendous step forward for researchers, and the knowledge gained about receptor-ligand interactions and signaling in this system may prove relevant in other diseases, as well.”

Surgery to remove heterotopic tissue is typically not beneficial to patients as it promotes additional episodes of heterotopic ossification. To test whether pharmacologic inhibition of activin A could prevent heterotopic ossification in these mice, the researchers developed a human antibody that targets activin A. Mice with mutant ACVR1 that were treated with this antibody did not develop heterotopic ossification up to 6 weeks after treatment. Episodes of aberrant bone formation can be triggered by tissue damage and inflammation, and activin A is released in response to injury and inflammation, so these findings suggest that activin A drives episodes of heterotopic ossification. Most generally, these findings highlight the growing potential of transgenic mice for modeling rare disorders and developing novel therapies.