Constitutively activated ALK2 and increased SMAD1/5 cooperatively induce bone morphogenetic protein signaling in fibrodysplasia ossificans progressiva.
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.
Fukuda
Toru
T
Division of Pathophysiology, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241, Japan.
Kohda
Masakazu
M
Kanomata
Kazuhiro
K
Nojima
Junya
J
Nakamura
Atsushi
A
Kamizono
Jyunji
J
Noguchi
Yasuo
Y
Iwakiri
Kiyofumi
K
Kondo
Takeo
T
Kurose
Junichi
J
Endo
Ken-ichi
K
Awakura
Takeshi
T
Fukushi
Junichi
J
Nakashima
Yasuharu
Y
Chiyonobu
Tomohiro
T
Kawara
Akira
A
Nishida
Yoshihiro
Y
Wada
Ikuo
I
Akita
Masumi
M
Komori
Tetsuo
T
Nakayama
Konosuke
K
Nanba
Akira
A
Maruki
Yuichi
Y
Yoda
Tetsuya
T
Tomoda
Hiroshi
H
Yu
Paul B
PB
Shore
Eileen M
EM
Kaplan
Frederick S
FS
Miyazono
Kohei
K
Matsuoka
Masaru
M
Ikebuchi
Kenji
K
Ohtake
Akira
A
Oda
Hiromi
H
Jimi
Eijiro
E
Owan
Ichiro
I
Okazaki
Yasushi
Y
Katagiri
Takenobu
T
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
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