Depletion of Mast Cells and Macrophages Impairs Heterotopic Ossification in an Acvr1 Mouse Model of Fibrodysplasia Ossificans Progressiva.

Heterotopic ossification (HO) is a clinical condition that often reduces mobility and diminishes quality of life for affected individuals. The most severe form of progressive HO occurs in those with fibrodysplasia ossificans progressiva (FOP; OMIM #135100), a genetic disorder caused by a recurrent heterozygous gain-of-function mutation (R206H) in the bone morphogenetic protein (BMP) type I receptor ACVR1/ALK2. In individuals with FOP, episodes of HO frequently follow injury. The first sign of active disease is commonly an inflammatory "flare-up" that precedes connective tissue degradation, progenitor cell recruitment, and endochondral HO. We used a conditional-on global knock-in mouse model expressing Acvr1 (referred to as Acvr1 ) to investigate the cellular and molecular inflammatory response in FOP lesions following injury. We found that the Acvr1 R206H mutation caused increased BMP signaling in posttraumatic FOP lesions and early divergence from the normal skeletal muscle repair program with elevated and prolonged immune cell infiltration. The proinflammatory cytokine response of TNFα, IL-1β, and IL-6 was elevated and prolonged in Acvr1 lesions and in Acvr1 mast cells. Importantly, depletion of mast cells and macrophages significantly impaired injury-induced HO in Acvr1 mice, reducing injury-induced HO volume by ∼50% with depletion of each cell population independently, and ∼75% with combined depletion of both cell populations. Together, our data show that the immune system contributes to the initiation and development of HO in FOP. Further, the expression of Acvr1 in immune cells alters cytokine expression and cellular response to injury and unveils novel therapeutic targets for treatment of FOP and nongenetic forms of HO. © 2017 American Society for Bone and Mineral Research.