Constitutively Activated ALK2 and Increased SMAD1/5 Cooperatively Induce Bone Morphogenetic Protein Signaling in Fibrodysplasia Ossificans Progressiva

Yoshihiro Nishida,Eileen M. Shore,Kenichi Endo ,Yasuharu Nakashima,Akira Nanba,Tsuyoshi Fukuda ,Hiroshi Tomoda,Frederick S. Kaplan,Takeo Kondo,Eijiro Jimi,Masumi Akita,Junichi Kurose,Yasuo Noguchi,Kazuhiro Kanomata,Masakazu Kohda,Hiromi Oda,Jun-Ichi Fukushi ,Tomohiro Chiyonobu,Jyunji Kamizono,Ikuo Wada,Ichiro Owan,Junya Nojima,Tetsuo Komori,Yasushi Okazaki,Makoto Matsuoka ,K. Iwakiri ,Tetsuya Yoda,Akira Ohtake,Konosuke Nakayama,Yuichi Maruki,Takenobu Katagiri,Takeshi Awakura,Atsushi Nakamura,Kohei Miyazono,Kenji Ikebuchi,Akira Kawara,Paul B. Yu

doi:10.1074/jbc.m801681200

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.

Highlights

These findings suggest that the heterotopic bone formation in Fibrodysplasia ossificans progressiva (FOP) may be induced by a constitutively activated bone morphogenetic protein (BMP) receptor signaling through Smad1 or Smad5
ALK2(R206H) Is a Constitutively Activated BMP Receptor— To examine functional changes of the mutant ALK2 identified in FOP, we examined its intracellular signaling in vitro
A recurrent mutation of 617G3 A in the ACVR1/ ALK2 gene was identified as the mutation responsible for FOP [21], a rare skeletal disorder associated with heterotopic bone formation in muscle and other soft connective tissues [1,2,3,4,5]

Summary

Introduction

A mutation involving a single amino acid substitution in a bone morphogenetic protein (BMP) type I receptor, ALK2, was identified in patients with FOP. This mutant receptor, ALK2(R206H), activates BMP signaling without ligand binding. ALK2(R206H) with Smad or Smad induced osteoblastic differentiation that could be inhibited by Smad 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 Smad or Smad. Gene transfer of Smad or inhibition of type I receptors with dorsomorphin may represent strategies for blocking the activity induced by ALK2(R206H) in FOP. Ectopic bone formation similar to that observed in FOP is induced by implantation of bone morphogenetic proteins (BMPs) into muscle tissue (6 – 8).

Methods

Results

Conclusion