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 Komori; Konosuke 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

doi:10.1074/jbc.M801681200

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 journal › Article › peer-review

134 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 language	English
Pages (from-to)	7149-7156
Number of pages	8
Journal	Journal of Biological Chemistry
Volume	284
Issue number	11
DOIs	https://doi.org/10.1074/jbc.M801681200
Publication status	Published - Mar 13 2009
Externally published	Yes

All Science Journal Classification (ASJC) codes

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

Constitutively activated ALK2 and increased SMAD1/5 cooperatively induce bone morphogenetic protein signaling in fibrodysplasia ossificans progressiva. / Fukuda, Toru; Kohda, Masakazu; Kanomata, Kazuhiro; Nojima, Junya; Nakamura, Atsushi; Kamizono, Jyunji; Noguchi, Yasuo; Iwakiri, Kiyofumi; Kondo, Takeo; Kurose, Junichi; Endo, Ken Ichi; Awakura, Takeshi; Fukushi, Junichi; Nakashima, Yasuharu; Chiyonobu, Tomohiro; Kawara, Akira; Nishida, Yoshihiro; Wada, Ikuo; Akita, Masumi; Komori, Tetsuo; Nakayama, Konosuke; Nanba, Akira; Maruki, Yuichi; Yoda, Tetsuya; Tomoda, Hiroshi; Yu, Paul B.; Kaplan, Frederick S.; Miyazono, Kohei; Matsuoka, Masaru; Ikebuchi, Kenji; Ohtake, Akira; Oda, Hiromi; Jimi, Eijiro; Owan, Ichiro; Okazaki, Yasushi; Katagiri, Takenobu.

In: Journal of Biological Chemistry, Vol. 284, No. 11, 13.03.2009, p. 7149-7156.

Research output: Contribution to journal › Article › peer-review

Fukuda, T, Kohda, M, Kanomata, K, Nojima, J, Nakamura, A, Kamizono, J, Noguchi, Y, Iwakiri, K, Kondo, T, Kurose, J, Endo, KI, Awakura, T, Fukushi, J, Nakashima, Y, Chiyonobu, T, Kawara, A, Nishida, Y, Wada, I, Akita, M, Komori, T, Nakayama, K, Nanba, A, Maruki, Y, Yoda, T, Tomoda, H, Yu, PB, Kaplan, FS, Miyazono, K, Matsuoka, M, Ikebuchi, K, Ohtake, A, Oda, H, Jimi, E, Owan, I, Okazaki, Y & Katagiri, T 2009, 'Constitutively activated ALK2 and increased SMAD1/5 cooperatively induce bone morphogenetic protein signaling in fibrodysplasia ossificans progressiva', Journal of Biological Chemistry, vol. 284, no. 11, pp. 7149-7156. https://doi.org/10.1074/jbc.M801681200

Fukuda, Toru ; Kohda, Masakazu ; Kanomata, Kazuhiro ; Nojima, Junya ; Nakamura, Atsushi ; Kamizono, Jyunji ; Noguchi, Yasuo ; Iwakiri, Kiyofumi ; Kondo, Takeo ; Kurose, Junichi ; Endo, Ken Ichi ; Awakura, Takeshi ; Fukushi, Junichi ; Nakashima, Yasuharu ; Chiyonobu, Tomohiro ; Kawara, Akira ; Nishida, Yoshihiro ; Wada, Ikuo ; Akita, Masumi ; Komori, Tetsuo ; Nakayama, Konosuke ; Nanba, Akira ; Maruki, Yuichi ; Yoda, Tetsuya ; Tomoda, Hiroshi ; Yu, Paul B. ; Kaplan, Frederick S. ; Miyazono, Kohei ; Matsuoka, Masaru ; Ikebuchi, Kenji ; Ohtake, Akira ; Oda, Hiromi ; Jimi, Eijiro ; Owan, Ichiro ; Okazaki, Yasushi ; Katagiri, Takenobu. / Constitutively activated ALK2 and increased SMAD1/5 cooperatively induce bone morphogenetic protein signaling in fibrodysplasia ossificans progressiva. In: Journal of Biological Chemistry. 2009 ; Vol. 284, No. 11. pp. 7149-7156.

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

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.",

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

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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

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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