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Nat Commun. 2018 Feb 2;9(1):471. doi: 10.1038/s41467-018-02872-2.

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

Author information

1
Department of Molecular and Cell Biology, University of Connecticut Stem Cell Institute, University of Connecticut, Storrs, CT, 06269, USA.
2
Department of Biological and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, MI, 48109, USA.
3
Alexion Pharmaceuticals, 100 College St, New Haven, CT, 06510, USA.
4
Department of Molecular and Cell Biology, University of Connecticut Stem Cell Institute, University of Connecticut, Storrs, CT, 06269, USA. david.goldhamer@uconn.edu.

Abstract

Fibrodysplasia 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 inĀ 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.

PMID:
29396429
PMCID:
PMC5797136
DOI:
10.1038/s41467-018-02872-2
[Indexed for MEDLINE]
Free PMC Article

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