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Constitutively activated ALK2 and increased SMAD1/5 cooperatively induce bone morphogenetic protein signaling in fibrodysplasia ossificans progressiva.
J Biol Chem. 2009 Mar 13; 284(11):7149-56.JB

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.

Authors+Show Affiliations

Division of Pathophysiology, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18684712

Citation

Fukuda, Toru, et al. "Constitutively Activated ALK2 and Increased SMAD1/5 Cooperatively Induce Bone Morphogenetic Protein Signaling in Fibrodysplasia Ossificans Progressiva." The Journal of Biological Chemistry, vol. 284, no. 11, 2009, pp. 7149-56.
Fukuda T, Kohda M, Kanomata K, et al. Constitutively activated ALK2 and increased SMAD1/5 cooperatively induce bone morphogenetic protein signaling in fibrodysplasia ossificans progressiva. J Biol Chem. 2009;284(11):7149-56.
Fukuda, T., Kohda, M., Kanomata, K., Nojima, J., Nakamura, A., Kamizono, J., Noguchi, Y., Iwakiri, K., Kondo, T., Kurose, J., Endo, K., 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. The Journal of Biological Chemistry, 284(11), 7149-56. https://doi.org/10.1074/jbc.M801681200
Fukuda T, et al. Constitutively Activated ALK2 and Increased SMAD1/5 Cooperatively Induce Bone Morphogenetic Protein Signaling in Fibrodysplasia Ossificans Progressiva. J Biol Chem. 2009 Mar 13;284(11):7149-56. PubMed PMID: 18684712.
* Article titles in AMA citation format should be in sentence-case
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 - Shore,Eileen M, 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, Y1 - 2008/08/06/ PY - 2008/8/8/pubmed PY - 2009/5/5/medline PY - 2008/8/8/entrez SP - 7149 EP - 56 JF - The Journal of biological chemistry JO - J Biol Chem VL - 284 IS - 11 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. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/18684712/Constitutively_activated_ALK2_and_increased_SMAD1/5_cooperatively_induce_bone_morphogenetic_protein_signaling_in_fibrodysplasia_ossificans_progressiva_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(20)32598-9 DB - PRIME DP - Unbound Medicine ER -