Activin-dependent signaling in fibro/adipogenic progenitors causes fibrodysplasia ossificans progressiva.
John B Lees-ShepardMasakazu YamamotoArpita A BiswasSean J StoesselSarah-Anne E NicholasCathy A CogswellParvathi M DevarakondaMichael J SchneiderSamantha M CumminsNicholas P LegendreShoko YamamotoVesa KaartinenJeffrey W HunterDavid J GoldhamerPublished in: Nature communications (2018)
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.
Keyphrases
- wild type
- pi k akt
- mesenchymal stem cells
- mouse model
- end stage renal disease
- cell therapy
- binding protein
- chronic kidney disease
- multiple sclerosis
- ejection fraction
- poor prognosis
- peritoneal dialysis
- bone marrow
- newly diagnosed
- stem cells
- high resolution
- prognostic factors
- gene expression
- copy number
- genome wide
- dna methylation
- oxidative stress
- dna binding