Activin-dependent signaling in fibro/adipogenic progenitors causes fibrodysplasia ossificans progressiva

• DOI: 10.1038/s41467-018-02872-2
• Publication Date: 2018-01-29T11:43:46Z
• Authors: John B. Lees-Shepard; Masakazu Yamamoto; Arpita A. Biswas; Sean J. Stoessel; Sarah-Anne E. Nic...; Cathy A. Cogswell; Parvathi M. Devar...; Michael J. Schneider; Samantha M. Cummins; Nicholas P. Legendre; Shoko Yamamoto; Vesa Kaartinen; Jeffrey W. Hunter; David J. Goldhamer
• Keywords: Male; Wound Healing; 0303 health sciences; Science; Stem Cells; Q; Mice, Transgenic; Article; Activins; Disease Models, Animal; 03 medical and health sciences; Myositis Ossificans; Osteogenesis; Animals; Female; Gene Knock-In Techniques; Muscle, Skeletal; Activin Receptors, Type I

AbstractFibrodysplasia ossificans progressiva (FOP) is a rare autosomal-dominant disorder characterized by progressive and profoundly disabling heterotopic ossification (HO). Here we show that fibro/adipogenic progenitors (FAPs) are a major cell-of-origin of HO in an accurate genetic mouse model of FOP (Acvr1 tnR206H ). Targeted expression of the disease-causing type I bone morphogenetic protein (BMP) receptor, ACVR1(R206H), to FAPs recapitulates the full spectrum of HO observed in FOP patients. ACVR1(R206H)-expressing FAPs, but not wild-type FAPs, activate osteogenic signaling in response to activin ligands. Conditional loss of the wild-type Acvr1 allele dramatically exacerbates FAP-directed HO, suggesting that mutant and wild-type ACVR1 receptor complexes compete for activin ligands or type II BMP receptor binding partners. Finally, systemic inhibition of activin A completely blocks HO and restores wild-type-like behavior to transplanted Acvr1 R206H/+ FAPs. Understanding the cells that drive HO may facilitate the development of cell-specific therapeutic approaches to inhibit catastrophic bone formation in FOP.