Journal
Science Translational Medicine
Volume 8, Issue 366, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aaf1090
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Funding
- US NIH [HL079943, AR057374, DK036836, HL100402]
- Brigham and Women's Hospital Cardiovascular Division T32 [HL007604]
- National Institute of Arthritis and Musculoskeletal and Skin Diseases P30 Center for Skeletal Research Core [AR066261]
- Department of Defense [MR140072]
- Harvard Stem Cell Institute Seed Award
- International FOP Association Competitive Grant Award
- Harvard Stem Cell Institute
- Pulmonary Hypertension Association Clinician Scientist Career Development Award
- Leducq Foundation Transatlantic Network of Excellence Award
- Howard Hughes Medical Institute Early Career Physician-Scientist Award
- Massachusetts Technology Transfer Award
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Fibrodysplasia ossificans progressiva (FOP), a congenital heterotopic ossification (HO) syndrome caused by gain-of-function mutations of bone morphogenetic protein (BMP) type I receptor ACVR1, manifests with progressive ossification of skeletal muscles, tendons, ligaments, and joints. In this disease, HO can occur in discrete flares, often triggered by injury or inflammation, or may progress incrementally without identified triggers. Mice harboring an Acvr1(R206H) knock-in allele recapitulate the phenotypic spectrum of FOP, including injury-responsive intramuscular HO and spontaneous articular, tendon, and ligament ossification. The cells that drive HO in these diverse tissues can be compartmentalized into two lineages: an Scx(+) tendon-derived progenitor that mediates endochondral HO of ligaments and joints without exogenous injury, and a muscle-resident interstitial Mx1(+) population that mediates intramuscular, injury-dependent endochondral HO. Expression of Acvr1(R206H) in either lineage confers aberrant gain of BMP signaling and chondrogenic differentiation in response to activin A and gives rise to mutation-expressing hypertrophic chondrocytes in HO lesions. Compared to Acvr1(R206H), expression of the man-made, ligand-independent ACVR1(Q207D) mutation accelerates and increases the penetrance of all observed phenotypes, but does not abrogate the need for antecedent injury in muscle HO, demonstrating the need for an injury factor in addition to enhanced BMP signaling. Both injury-dependent intramuscular and spontaneous ligament HO in Acvr(1R206H) knock-in mice were effectively controlled by the selective ACVR1 inhibitor LDN-212854. Thus, diverse phenotypes of HO found in FOP are rooted in cell-autonomous effects of dysregulated ACVR1 signaling in nonoverlapping tissue-resident progenitor pools that may be addressed by systemic therapy or by modulating injury-mediated factors involved in their local recruitment.
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