Unknown

Dataset Information

0

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


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 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.

SUBMITTER: Lees-Shepard JB 

PROVIDER: S-EPMC5797136 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

altmetric image

Publications


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 in an accurate genetic mouse model of FOP (Acvr1 <sup>tnR206H</sup> ). 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 patien  ...[more]

Similar Datasets

| S-EPMC9197527 | biostudies-literature
| S-EPMC6164166 | biostudies-literature
| S-EPMC5669572 | biostudies-literature
| S-EPMC10813747 | biostudies-literature
| S-EPMC6680371 | biostudies-literature
| S-EPMC10526456 | biostudies-literature
| S-EPMC6145951 | biostudies-literature
| S-EPMC8391109 | biostudies-literature
| S-EPMC3894630 | biostudies-literature
| S-EPMC6235670 | biostudies-literature