Abstract
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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Activin Receptors, Type I / genetics
-
Activin Receptors, Type I / metabolism*
-
Amino Acid Substitution
-
Animals
-
Bone Morphogenetic Protein Receptors, Type I / genetics
-
Bone Morphogenetic Protein Receptors, Type I / metabolism*
-
Cell Differentiation*
-
Cell Line
-
Female
-
Humans
-
Male
-
Matrix Metalloproteinases, Secreted / genetics
-
Matrix Metalloproteinases, Secreted / metabolism*
-
Mice
-
Mutation, Missense
-
Myositis Ossificans / genetics
-
Myositis Ossificans / metabolism*
-
Myositis Ossificans / pathology
-
Osteoblasts / metabolism*
-
Osteoblasts / pathology
-
Osteogenesis*
-
Pyrazoles / pharmacology
-
Pyrimidines / pharmacology
-
Signal Transduction*
-
Smad1 Protein / genetics
-
Smad1 Protein / metabolism*
-
Smad5 Protein / genetics
-
Smad5 Protein / metabolism*
-
Smad7 Protein / genetics
-
Smad7 Protein / metabolism
Substances
-
Pyrazoles
-
Pyrimidines
-
SMAD1 protein, human
-
SMAD5 protein, human
-
SMAD7 protein, human
-
Smad1 Protein
-
Smad1 protein, mouse
-
Smad5 Protein
-
Smad5 protein, mouse
-
Smad7 Protein
-
Smad7 protein, mouse
-
dorsomorphin
-
ACVR1 protein, human
-
Activin Receptors, Type I
-
Acvr1 protein, mouse
-
Bone Morphogenetic Protein Receptors, Type I
-
Matrix Metalloproteinases, Secreted