Constitutively Activated ALK2 and Increased SMAD1/5 Cooperatively Induce Bone Morphogenetic Protein Signaling in Fibrodysplasia Ossificans Progressiva

被引：169

作者：

Fukuda, Toru ^{[1
,3
]}

Kohda, Masakazu ^{[2
]}

Kanomata, Kazuhiro ^{[1
]}

Nojima, Junya ^{[1
,17
]}

Nakamura, Atsushi ^{[1
]}

Kamizono, Jyunji ^{[4
]}

Noguchi, Yasuo ^{[5
]}

Iwakiri, Kiyofumi ^{[6
]}

Kondo, Takeo ^{[7
]}

Kurose, Junichi ^{[8
]}

Endo, Ken-ichi ^{[9
]}

Awakura, Takeshi ^{[10
]}

Fukushi, Junichi ^{[11
]}

Nakashima, Yasuharu ^{[11
,33
]}

Chiyonobu, Tomohiro ^{[12
]}

Kawara, Akira ^{[13
]}

Nishida, Yoshihiro ^{[14
,15
]}

Wada, Ikuo ^{[16
]}

Akita, Masumi ^{[3
,24
]}

Komori, Tetsuo ^{[3
,20
]}

Nakayama, Konosuke ^{[3
,19
]}

Nanba, Akira ^{[3
,18
]}

Maruki, Yuichi ^{[3
,25
]}

Yoda, Tetsuya ^{[3
,17
]}

Tomoda, Hiroshi ^{[3
,27
]}

Yu, Paul B. ^{[28
,29
]}

Shore, Eileen M. ^{[30
]}

Kaplan, Frederick S. ^{[30
]}

Miyazono, Kohei ^{[3
,26
]}

Matsuoka, Masaru ^{[23
]}

Ikebuchi, Kenji ^{[3
,23
]}

Ohtake, Akira ^{[3
,22
]}

Oda, Hiromi ^{[3
,21
]}

Jimi, Eijiro ^{[3
,31
]}

Owan, Ichiro ^{[3
,32
]}

Okazaki, Yasushi ^{[2
,3
]}

Katagiri, Takenobu ^{[1
,3
]}

机构：

[1] Saitama Med Univ, Res Ctr Genom Med, Div Pathophysiol, Hidaka, Saitama 3501241, Japan

[2] Saitama Med Univ, Res Ctr Genom Med, Div Translat Res, Hidaka, Saitama 3501241, Japan

[3] Saitama Med Univ, Project Clin & Basic Res FOP, Hidaka, Saitama 3501241, Japan

[4] Kitakyusyu City Yahata Hosp, Dept Pediat Emergency, Yahatahigashi Ku, Kitakyushu, Fukuoka 8058534, Japan

[5] Saga Prefectural Hosp Koseikan, Dept Orthoped Surg, Saga 8408571, Japan

[6] Nagayoshi Orthoped Clin, Miyazaki 8800951, Japan

[7] Tohoku Univ, Grad Sch Med, Dept Phys Med & Rehabil, Aoba Ku, Sendai, Miyagi 9808474, Japan

[8] Senjyudo Hosp, Dept Orthoped Surg, Gifu 5008862, Japan

[9] Endo Clin, Kodaira, Tokyo 1870035, Japan

[10] Awakura Clin, Wajima, Ishiwawa 9280246, Japan

[11] Kyushu Univ, Fac Med, Dept Orthoped Surg, Higashi Ku, Fukuoka 8128582, Japan

[12] Akashi Municipal Hosp, Dept Pediat, Akashi, Hyogo 6738501, Japan

[13] Kawara Clin, Higashinada Ku, Kobe, Hyogo 6580051, Japan

[14] Nagoya Univ, Grad Sch, Dept Orthopaed Surg, Showa Ku, Nagoya, Aichi 4668550, Japan

[15] Sch Med, Showa Ku, Nagoya, Aichi 4668550, Japan

[16] Nagoya City Univ Hosp, Dept Rehabil, Mizuho Ku, Nagoya, Aichi 4678602, Japan

[17] Saitama Med Univ, Dept Oral & Maxillofacial Surg, Moroyama, Saitama 3500495, Japan

[18] Saitama Med Univ, Dept Obstet & Gynecol, Moroyama, Saitama 3500495, Japan

[19] Saitama Med Univ, Dept Endocrinol & Diabet, Moroyama, Saitama 3500495, Japan

[20] Saitama Med Univ, Dept Neurol, Moroyama, Saitama 3500495, Japan

[21] Saitama Med Univ, Dept Orthoped Surg, Moroyama, Saitama 3500495, Japan

[22] Saitama Med Univ, Dept Pediat, Moroyama, Saitama 3500495, Japan

[23] Saitama Med Univ, Dept Lab Med, Moroyama, Saitama 3500495, Japan

[24] Saitama Med Univ, Biomed Res Ctr, Div Morphol Sci, Moroyama, Saitama 3500495, Japan

[25] Saitama Neuropsychiat Inst, Dept Neurol, Chuo Ku, Saitama 3388577, Japan

[26] Univ Tokyo, Grad Sch Med, Dept Mol Pathol, Bunkyo Ku, Tokyo 1130033, Japan

[27] Kitasato Univ, Sch Pharmaceut Sci, Minato Ku, Tokyo 1080023, Japan

[28] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol,Dept Med, Boston, MA 02129 USA

[29] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr,Dept Med, Boston, MA 02129 USA

[30] Univ Penn, Sch Med, Dept Orthoped Surg, Ctr Res Fibrodysplasia Ossificans Progress & Rela, Philadelphia, PA 19104 USA

[31] Kyushu Dent Coll, Dept Biosci, Div Mol Signaling & Biochem, Kokurakita Ku, Kitakyushu, Fukuoka 8038580, Japan

[32] Univ Ryukyus, Fac Med, Dept Orthoped Surg, Nishihara, Okinawa 9030215, Japan

[33] Minist Hlth Labour & Welf, Res Comm Fibrodysplasia Ossificans Progress, Bunkyo Ku, Tokyo 1138655, Japan

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2009年 / 284卷 / 11期

关键词：

I RECEPTORS; HETEROTOPIC OSSIFICATION; NATURAL-HISTORY; MESSENGER-RNA; ACTIVIN-A; IDENTIFICATION; DIFFERENTIATION; PATHWAY; DYSREGULATION; INJECTION;

D O I：

10.1074/jbc.M801681200

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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.

引用

页码：7149 / 7156

页数：8

共 43 条

[1]

Induction of inhibitory Smad6 and Smad7 mRNA by TGF-β family members [J].

Afrakhte, M ;

Morén, A ;

Jossan, S ;

Itoh, S ;

Westermark, B ;

Heldin, CH ;

Heldin, NE ;

ten Dijke, P .

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1998, 249 (02) :505-511

[2]

Constitutively active BMP type I receptors transduce BMP-2 signals without the ligand in C2C12 myoblasts [J].

Akiyama, S ;

Katagiri, T ;

Namiki, M ;

Yamaji, N ;

Yamamoto, N ;

Miyama, K ;

Shibuya, H ;

Ueno, N ;

Wozney, JM ;

Suda, T .

EXPERIMENTAL CELL RESEARCH, 1997, 235 (02) :362-369

[3]

Aoki H, 2001, J CELL SCI, V114, P1483

[4]

IDENTIFICATION OF HUMAN ACTIVIN AND TGF-BETA TYPE-I RECEPTORS THAT FORM HETEROMERIC KINASE COMPLEXES WITH TYPE-II RECEPTORS [J].

ATTISANO, L ;

CARCAMO, J ;

VENTURA, F ;

WEIS, FMB ;

MASSAGUE, J ;

WRANA, JL .

CELL, 1993, 75 (04) :671-680

[5]

THE NATURAL-HISTORY OF HETEROTOPIC OSSIFICATION IN PATIENTS WHO HAVE FIBRODYSPLASIA OSSIFICANS PROGRESSIVA - A STUDY OF 44 PATIENTS [J].

COHEN, RB ;

HAHN, GV ;

TABAS, JA ;

PEEPER, J ;

LEVITZ, CL ;

SANDO, A ;

SANDO, N ;

ZASLOFF, M ;

KAPLAN, FS .

JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME, 1993, 75A (02) :215-219

[6]

FIBRODYSPLASIA OSSIFICANS PROGRESSIVA - THE CLINICAL-FEATURES AND NATURAL-HISTORY OF 34 PATIENTS [J].

CONNOR, JM ;

EVANS, DAP .

JOURNAL OF BONE AND JOINT SURGERY-BRITISH VOLUME, 1982, 64 (01) :76-83

[7]

Bone morphogenetic protein-9 is a circulating vascular quiescence factor [J].

David, Laurent ;

Mallet, Christine ;

Keramidas, Michelle ;

Lamande, Noel ;

Gasc, Jean-Marie ;

Dupuis-Girod, Sophie ;

Plauchu, Henri ;

Feige, Jean-Jacques ;

Bailly, Sabine .

CIRCULATION RESEARCH, 2008, 102 (08) :914-922

[8]

Low turnover osteodystrophy and vascular calcification are amenable to skeletal anabolism in an animal model of chronic kidney disease and the metabolic syndrome [J].

Davies, MR ;

Lund, RJ ;

Mathew, S ;

Hruska, KA .

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2005, 16 (04) :917-928

[9]

Dysregulation of the BMP-p38 MAPK signaling pathway in cells from patients with fibrodysplasia ossificans progressiva (FOP) [J].

Fiori, Jennifer L. ;

Billings, Paul C. ;

Serrano de la Pena, Lourdes ;

Kaplan, Frederick S. ;

Shore, Eileen M. .

JOURNAL OF BONE AND MINERAL RESEARCH, 2006, 21 (06) :902-909

[10]

Bone morphogenetic protein 2/4 in early fibromatous lesions of fibrodysplasia ossificans progressiva [J].

Gannon, FH ;

Kaplan, FS ;

Olmsted, E ;

Finkel, GC ;

Zasloff, MA ;

Shore, E .

HUMAN PATHOLOGY, 1997, 28 (03) :339-343

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