RESUMO
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.
Assuntos
Receptores de Ativinas Tipo I/metabolismo , Receptores de Proteínas Morfogenéticas Ósseas Tipo I/metabolismo , Diferenciação Celular , Metaloproteinases da Matriz Secretadas/metabolismo , Miosite Ossificante/metabolismo , Osteoblastos/metabolismo , Osteogênese , Transdução de Sinais , Proteína Smad1/metabolismo , Proteína Smad5/metabolismo , Receptores de Ativinas Tipo I/genética , Substituição de Aminoácidos , Animais , Receptores de Proteínas Morfogenéticas Ósseas Tipo I/genética , Linhagem Celular , Feminino , Humanos , Masculino , Metaloproteinases da Matriz Secretadas/genética , Camundongos , Mutação de Sentido Incorreto , Miosite Ossificante/genética , Miosite Ossificante/patologia , Osteoblastos/patologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Proteína Smad1/genética , Proteína Smad5/genética , Proteína Smad7/genética , Proteína Smad7/metabolismoRESUMO
Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant congenital disorder characterized by progressive heterotopic bone formation in muscle tissues. A common mutation among FOP patients has been identified in ALK2, ALK2(R206H), which encodes a constitutively active bone morphogenetic protein (BMP) receptor. Recently, a unique mutation of ALK2, ALK2(G356D), was identified to be a novel mutation in a Japanese FOP patient who had unique clinical features. Over-expression of ALK2(G356D) induced phosphorylation of Smad1/5/8 and activated Id1-luc and alkaline phosphatase activity in myoblasts. However, the over-expression failed to activate phosphorylation of p38, ERK1/2, and CAGA-luc activity. These ALK2(G356D) activities were weaker than those of ALK2(R206H), and they were suppressed by a specific inhibitor of the BMP-regulated Smad pathway. These findings suggest that ALK2(G356D) induces heterotopic bone formation via activation of a BMP-regulated Smad pathway. The quantitative difference between ALK2(G356D) and ALK2(R206H) activities may have caused the phenotypic differences in these patients.
