Constitutively Activated ALK2 and Increased SMAD1/5 Cooperatively Induce Bone Morphogenetic Protein Signaling in Fibrodysplasia Ossificans Progressiva*S⃞
| Autor: | Tetsuya Yoda, Konosuke Nakayama, Atsushi Nakamura, Eileen M. Shore, Junya Nojima, Junichi Kurose, Akira Kawara, Akira Ohtake, Toru Fukuda, Kiyofumi Iwakiri, Takeo Kondo, Takeshi Awakura, Frederick S. Kaplan, Yasuo Noguchi, Masumi Akita, Yuichi Maruki, Jun Ichi Fukushi, Masaru Matsuoka, Kenji Ikebuchi, Ikuo Wada, Takenobu Katagiri, Ken-ichi Endo, Tetsuo Komori, Eijiro Jimi, Masakazu Kohda, Ichiro Owan, Tomohiro Chiyonobu, Yoshihiro Nishida, Hiromi Oda, Yasushi Okazaki, Kohei Miyazono, Yasuharu Nakashima, Kazuhiro Kanomata, Paul B. Yu, Jyunji Kamizono, Hiroshi Tomoda, Akira Nanba |
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| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Male
Smad5 Protein medicine.medical_specialty animal structures Cellular differentiation Mutation Missense ACVR1 Biology Bone morphogenetic protein Biochemistry Cell Line Smad1 Protein Smad7 Protein Mice Molecular Basis of Cell and Developmental Biology Osteogenesis Internal medicine Matrix Metalloproteinases Secreted medicine Animals Humans Receptor Molecular Biology Bone Morphogenetic Protein Receptors Type I Osteoblasts Cell Differentiation Cell Biology Myositis ossificans medicine.disease BMPR2 Cell biology Endocrinology Pyrimidines Amino Acid Substitution Myositis Ossificans Fibrodysplasia ossificans progressiva embryonic structures Pyrazoles Female Signal transduction Activin Receptors Type I Signal Transduction |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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