Overexpression of Wild-Type ACVR1 in Fibrodysplasia Ossificans Progressiva Mice Rescues Perinatal Lethality and Inhibits Heterotopic Ossification

Abstract

Fibrodysplasia ossificans progressiva (FOP) is a devastating disease of progressive heterotopic bone formation for which effective treatments are currently unavailable. FOP is caused by dominant gain-of-function mutations in the receptor ACVR1 (also known as ALK2), which render the receptor inappropriately responsive to activin ligands. In previous studies, we developed a genetic mouse model of FOP that recapitulates most clinical aspects of the disease. In this model, genetic loss of the wild-type Acvr1 allele profoundly exacerbated heterotopic ossification, suggesting the hypothesis that the stoichiometry of wild-type and mutant receptors dictates disease severity. Here, we tested this model by producing FOP mice that conditionally overexpress human wild-type ACVR1. Injury-induced heterotopic ossification (HO) was completely blocked in FOP mice when expression of both the mutant and wild-type receptor were targeted to Tie2-positive cells, which includes fibro/adipogenic progenitors (FAPs). Perinatal lethality of Acvr1 R206H/+ mice was rescued by constitutive ACVR1 overexpression, and these mice survived to adulthood at predicted Mendelian frequencies. Constitutive overexpression of ACVR1 also provided protection from spontaneous abnormal skeletogenesis, and the incidence and severity of injury-induced HO in these mice was dramatically reduced. Analysis of pSMAD1/5/8 signaling both in cultured cells and in vivo indicates that ACVR1 overexpression functions cell-autonomously by reducing osteogenic signaling in response to activin A. We propose that ACVR1 overexpression inhibits HO by decreasing the abundance of ACVR1(R206H)-containing signaling complexes at the cell surface while increasing the representation of activin-A-bound non-signaling complexes comprised of wild-type ACVR1.

Reduced GS Domain Serine/Threonine Requirements of Fibrodysplasia Ossificans Progressiva Mutant Type I BMP Receptor ACVR1 in the Zebrafish

“…These data support the idea that FOP-ACVR1 signals more efficiently with its canonical BMP ligand-receptor complex components than without. (53) Our results and others support that phosphorylation of the GS domain is required for activation of ACVR1-R206H, suggesting an important role for phosphorylation by type II BMP receptors. (27)(28)(29) Previous studies, however, showed that ACVR1-R206H and the constitutively active ACVR1-Q207D receptor could signal with kinase dead type II receptors, (29) supporting the idea that while type II receptors are required for signaling, their kinase activity is dispensable.…”

“…The ability of FOP‐ACVR1 to signal in the absence of ligand and Bmpr1 suggests the ability to signal in the absence of a BMP ligand‐receptor complex. However, in a genetic mouse model of FOP, WT‐ACVR1 OE lessens the severity of the phenotype, ( 53 ) presumably through competition for BMP ligand‐receptor components with ACVR1‐R206H. These data support the idea that FOP‐ACVR1 signals more efficiently with its canonical BMP ligand‐receptor complex components than without.…”

Reduced GS domain serine/threonine requirements of Fibrodysplasia Ossificans Progressiva mutant type I BMP receptor ACVR1 in the zebrafish

“…However, in a genetic mouse model of FOP, WT-ACVR1 overexpression lessens the severity of the phenotype 48 , presumably through competition for BMP ligandreceptor components with ACVR1-R206H. These data support that FOP-ACVR1 signals more efficiently with its canonical BMP ligand-receptor complex components than without 48 . Our results and others support that phosphorylation of the GS domain is required for activation of ACVR1-R206H, suggesting an important role for phosphorylation by type II BMP receptors [27][28][29] .…”

“…The ability of FOP-ACVR1 to signal in the absence of ligand and Bmpr1 suggests the ability to signal in the absence of a BMP ligand-receptor complex. However, in a genetic mouse model of FOP, WT-ACVR1 overexpression lessens the severity of the phenotype 48 , presumably through competition for BMP ligandreceptor components with ACVR1-R206H. These data support that FOP-ACVR1 signals more efficiently with its canonical BMP ligand-receptor complex components than without 48 .…”

Shedding Light on Bone Morphogenetic Protein (BMP) Signaling Modifiers to Modulate Fibrodysplasia Ossificans Progressiva Severity

“…In this issue, Wentworth and colleagues 17 and Yamamoto and colleagues 18 provide new insight on FOP pathophysiology pointing to possible future new therapeutic targets.…”