Constitutively activated ALK2 and increased SMAD1/5 cooperatively induce bone morphogenetic protein signaling in fibrodysplasia ossificans progressiva

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

Research output: Contribution to journalArticle

129 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)7149-7156
Number of pages8
JournalJournal of Biological Chemistry
Volume284
Issue number11
DOIs
Publication statusPublished - 2009 Mar 13

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Fukuda, T., Kohda, M., Kanomata, K., Nojima, J., Nakamura, A., Kamizono, J., Noguchi, Y., Iwakiri, K., Kondo, T., Kurose, J., Endo, K. I., Awakura, T., Fukushi, J., Nakashima, Y., Chiyonobu, T., Kawara, A., Nishida, Y., Wada, I., Akita, M., ... Katagiri, T. (2009). Constitutively activated ALK2 and increased SMAD1/5 cooperatively induce bone morphogenetic protein signaling in fibrodysplasia ossificans progressiva. Journal of Biological Chemistry, 284(11), 7149-7156. https://doi.org/10.1074/jbc.M801681200