ABSTRACT
Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant congenital disorder characterized by progressive heterotopic ossification in muscle tissues. Constitutively activated mutants of a bone morphogenetic protein (BMP) receptor, ALK2, have been identified in patients with FOP. Recently, a novel ALK2 mutation, L196P, was found in the most benign case of FOP reported thus far. In the present study, we examined the biological activities of ALK2(L196P) in vitro. Over-expression of ALK2(L196P) induced BMP-specific activities, including the suppression of myogenesis, the induction of alkaline phosphatase activity, increased BMP-specific luciferase reporter activity, and increased phosphorylation of Smad1/5 but not Erk1/2 or p38. The activities of ALK2(L196P) were higher than those of ALK2(G356D), another mutant ALK2 allele found in patients with FOP and were equivalent to those of ALK2(R206H), a typical mutation found in patients with FOP. ALK2(L196P) was equally or more resistant to inhibitors in comparison to ALK2(R206H). These findings suggest that ALK2(L196P) is an activated BMP receptor equivalent to ALK2(R206H) and that ALK2(L196P) activity may be suppressed in vivo by a novel molecular mechanism in patients with this mutation.
Subject(s)
Activin Receptors, Type I/metabolism , Bone Morphogenetic Proteins/metabolism , Mutation , Myositis Ossificans/genetics , Myositis Ossificans/metabolism , Activin Receptors, Type I/antagonists & inhibitors , Activin Receptors, Type I/genetics , Animals , Cell Differentiation , Cell Line , Humans , Mice , Osteoblasts/cytology , Osteoblasts/metabolism , Osteoblasts/physiology , Signal Transduction , Smad Proteins/metabolismABSTRACT
Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder characterized by progressive heterotopic bone formation in skeletal muscle tissue. In 2007, FOP was authorized as one of the Intractable Disorders by the Ministry of Health, Labour and Welfare of Japan. The Research Committee on FOP is working on the molecular mechanisms underlying heterotopic bone formation and the development of new treatments for FOP.
Subject(s)
Bone Morphogenetic Proteins/physiology , Myositis Ossificans , Signal Transduction/physiology , Transforming Growth Factor beta/physiology , Activin Receptors, Type I/genetics , Activin Receptors, Type I/metabolism , Drug Discovery , Genes, Dominant , Humans , Molecular Targeted Therapy , Mutation , Myositis Ossificans/drug therapy , Myositis Ossificans/genetics , Pyrazoles/pharmacology , Pyrazoles/therapeutic use , Pyrimidines/pharmacology , Pyrimidines/therapeutic useABSTRACT
Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder characterized by congenital malformation of the great toes and by progressive heterotopic bone formation in muscle tissue. Recently, a mutation involving a single amino acid substitution in a bone morphogenetic protein (BMP) type I receptor, ALK2, was identified in patients with FOP. We report here that the identical mutation, R206H, was observed in 19 Japanese patients with sporadic FOP. This mutant receptor, ALK2(R206H), activates BMP signaling without ligand binding. Moreover, expression of Smad1 and Smad5 was up-regulated in response to muscular injury. ALK2(R206H) with Smad1 or Smad5 induced osteoblastic differentiation that could be inhibited by Smad7 or dorsomorphin. Taken together, these findings suggest that the heterotopic bone formation in FOP may be induced by a constitutively activated BMP receptor signaling through Smad1 or Smad5. Gene transfer of Smad7 or inhibition of type I receptors with dorsomorphin may represent strategies for blocking the activity induced by ALK2(R206H) in FOP.
