TY - JOUR
T1 - Constitutively activated ALK2 and increased SMAD1/5 cooperatively induce bone morphogenetic protein signaling in fibrodysplasia ossificans progressiva
AU - Fukuda, Toru
AU - Kohda, Masakazu
AU - Kanomata, Kazuhiro
AU - Nojima, Junya
AU - Nakamura, Atsushi
AU - Kamizono, Jyunji
AU - Noguchi, Yasuo
AU - Iwakiri, Kiyofumi
AU - Kondo, Takeo
AU - Kurose, Junichi
AU - Endo, Ken Ichi
AU - Awakura, Takeshi
AU - Fukushi, Junichi
AU - Nakashima, Yasuharu
AU - Chiyonobu, Tomohiro
AU - Kawara, Akira
AU - Nishida, Yoshihiro
AU - Wada, Ikuo
AU - Akita, Masumi
AU - Komori, Tetsuo
AU - Nakayama, Konosuke
AU - Nanba, Akira
AU - Maruki, Yuichi
AU - Yoda, Tetsuya
AU - Tomoda, Hiroshi
AU - Yu, Paul B.
AU - Kaplan, Frederick S.
AU - Miyazono, Kohei
AU - Matsuoka, Masaru
AU - Ikebuchi, Kenji
AU - Ohtake, Akira
AU - Oda, Hiromi
AU - Jimi, Eijiro
AU - Owan, Ichiro
AU - Okazaki, Yasushi
AU - Katagiri, Takenobu
N1 - Copyright:
Copyright 2009 Elsevier B.V., All rights reserved.
PY - 2009/3/13
Y1 - 2009/3/13
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M801681200
DO - 10.1074/jbc.M801681200
M3 - Article
C2 - 18684712
AN - SCOPUS:65449139561
VL - 284
SP - 7149
EP - 7156
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 11
ER -