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 (Acvr1tnR206H). 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 Acvr1R206H/+ FAPs. Understanding the cells that drive HO may facilitate the development of cell-specific therapeutic approaches to inhibit catastrophic bone formation in FOP.
Highlights
Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal-dominant disorder characterized by progressive and profoundly disabling heterotopic ossification (HO)
Using lineage tracing and intramuscular injection of BMP2 as a mouse model for HO, we previously identified a progenitor population, lineage marked by expression of Tie2-Cre[10], that is a major cell-of-origin for BMP2-induced endochondral bone formation[11,12]
Previous studies have largely used cell culture and in vivo models of HO that rely on exposure of wild-type cells to non-physiological levels of osteogenic bone morphogenetic protein (BMP), or over-expression of ACVR1(R206H) or ACVR1(Q207D)[30], a constitutively active, ligand-independent engineered receptor that has not been observed in the FOP patient population[11,12,31,38,39,40,41,42]
Summary
Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal-dominant disorder characterized by progressive and profoundly disabling heterotopic ossification (HO). Progressive ossification of skeletal muscle and associated soft tissues is the defining clinical manifestation of fibrodysplasia ossificans progressiva (FOP), a rare autosomaldominant disorder caused by mutations in the type I BMP receptor, ACVR1 (ALK2)[1]. We developed a conditional knockin model of FOP, in which expression of Acvr1R206H from the endogenous Acvr[1] locus is dependent on Cre-mediated recombination Using this accurate genetic model of FOP, we demonstrate that FAPs are a major offending cell type for both injury-induced and spontaneous HO, consistent with the recent study of Dey et al.[19], who postulated that HO progenitors in FOP represent “reprogrammed” FAPs. Further, we show by lineage analysis that Acvr1R206H functions cell-autonomously in FAP-directed endochondral bone formation. Identifying the cells responsible for HO may facilitate development of celltargeted therapeutic approaches for FOP, complementing ongoing drug development strategies based on inhibition of activin A8,20, ACVR1 kinase activity[19] and cartilage differentiation[21,22,23]
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