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.
authors.affiliation: Division of Pathophysiology, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Fukuda
authors.forename: Masakazu
authors.initials: M
authors.lastname: Kohda
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kanomata
authors.forename: Junya
authors.initials: J
authors.lastname: Nojima
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nakamura
authors.forename: Jyunji
authors.initials: J
authors.lastname: Kamizono
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Noguchi
authors.forename: Kiyofumi
authors.initials: K
authors.lastname: Iwakiri
authors.forename: Takeo
authors.initials: T
authors.lastname: Kondo
authors.forename: Junichi
authors.initials: J
authors.lastname: Kurose
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Endo
authors.forename: Takeshi
authors.initials: T
authors.lastname: Awakura
authors.forename: Junichi
authors.initials: J
authors.lastname: Fukushi
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Nakashima
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Chiyonobu
authors.forename: Akira
authors.initials: A
authors.lastname: Kawara
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Nishida
authors.forename: Ikuo
authors.initials: I
authors.lastname: Wada
authors.forename: Masumi
authors.initials: M
authors.lastname: Akita
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Komori
authors.forename: Konosuke
authors.initials: K
authors.lastname: Nakayama
authors.forename: Akira
authors.initials: A
authors.lastname: Nanba
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Maruki
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Yoda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tomoda
authors.forename: Paul B
authors.initials: PB
authors.lastname: Yu
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Shore
authors.forename: Frederick S
authors.initials: FS
authors.lastname: Kaplan
authors.forename: Kohei
authors.initials: K
authors.lastname: Miyazono
authors.forename: Masaru
authors.initials: M
authors.lastname: Matsuoka
authors.forename: Kenji
authors.initials: K
authors.lastname: Ikebuchi
authors.forename: Akira
authors.initials: A
authors.lastname: Ohtake
authors.forename: Hiromi
authors.initials: H
authors.lastname: Oda
authors.forename: Eijiro
authors.initials: E
authors.lastname: Jimi
authors.forename: Ichiro
authors.initials: I
authors.lastname: Owan
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Okazaki
authors.forename: Takenobu
authors.initials: T
authors.lastname: Katagiri
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics / Q000378:metabolism*; D019943:Amino Acid Substitution; D000818:Animals; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D005260:Female; D006801:Humans; D008297:Male; D053505:Matrix Metalloproteinases, Secreted / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D020125:Mutation, Missense; D009221:Myositis Ossificans / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology; D010012:Osteogenesis; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction; D051898:Smad1 Protein / Q000235:genetics / Q000378:metabolism*; D051902:Smad5 Protein / Q000235:genetics / Q000378:metabolism*; D051906:Smad7 Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D011720:Pyrazoles; D011743:Pyrimidines; C497399:SMAD1 protein, human; C497797:SMAD5 protein, human; C497806:SMAD7 protein, human; D051898:Smad1 Protein; C497401:Smad1 protein, mouse; D051902:Smad5 Protein; C497798:Smad5 protein, mouse; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; C516138:dorsomorphin; C425423:ACVR1 protein, human; D030201:Activin Receptors, Type I; C498943:Acvr1 protein, mouse; D052005:Bone Morphogenetic Protein Receptors, Type I; D053505:Matrix Metalloproteinases, Secreted