Dual roles of smad proteins in the conversion from myoblasts to osteoblastic cells by bone morphogenetic proteins.
Bone morphogenetic proteins (BMPs) induce ectopic bone formation in muscle tissue in vivo and convert myoblasts such that they differentiate into osteoblastic cells in vitro. We report here that constitutively active Smad1 induced osteoblastic differentiation of C2C12 myoblasts in cooperation with Smad4 or Runx2. In floxed Smad4 mice-derived cells, Smad4 ablation partially suppressed BMP-4-induced osteoblast differentiation. In contrast, the BMP-4-induced inhibition of myogenesis was lost by Smad4 ablation and restored by Smad4 overexpression. A nuclear zinc finger protein, E4F1, was identified as a possible component of the Smad4 complex that suppresses myogenic differentiation in response to BMP signaling. In the presence of Smad4, E4F1 stimulated the expression of Ids. Taken together, these findings suggest that the Smad signaling pathway may play a dual role in the BMP-induced conversion of myoblasts to osteoblastic cells.
Nojima
Junya
J
Divisions of Pathophysiology, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241; Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Saitama Medical University, 38 Moro Hongo, Moroyama-machi, Iruma-gun, Saitama 350-0495.
Kanomata
Kazuhiro
K
Divisions of Pathophysiology, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241.
Takada
Yumi
Y
Department of Biochemistry, School of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-5555.
Fukuda
Toru
T
Divisions of Pathophysiology, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241.
Kokabu
Shoichiro
S
Divisions of Pathophysiology, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241; Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Saitama Medical University, 38 Moro Hongo, Moroyama-machi, Iruma-gun, Saitama 350-0495.
Ohte
Satoshi
S
Divisions of Pathophysiology, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241.
Takada
Takatora
T
Department of Biochemistry, School of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-5555.
Tsukui
Tohru
T
Divisions of Experimental Animal Laboratory, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241.
Yamamoto
Takamasa S
TS
Division of Morphogenesis, Department of Developmental Biology, National Institute for Basic Biology, 38 Nishigonaka, Myodaiji, Okazaki, Aichi 444-8585, Japan.
Sasanuma
Hiroki
H
Divisions of Pathophysiology, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241.
Yoneyama
Katsumi
K
Divisions of Pathophysiology, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241.
Ueno
Naoto
N
Division of Morphogenesis, Department of Developmental Biology, National Institute for Basic Biology, 38 Nishigonaka, Myodaiji, Okazaki, Aichi 444-8585, Japan.
Okazaki
Yasushi
Y
Divisions of Functional Genomics and System Research, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241.
Kamijo
Ryutaro
R
Department of Biochemistry, School of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-5555.
Yoda
Tetsuya
T
Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Saitama Medical University, 38 Moro Hongo, Moroyama-machi, Iruma-gun, Saitama 350-0495.
Katagiri
Takenobu
T
Divisions of Pathophysiology, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241. Electronic address: katagiri@saitama-med.ac.jp.
D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D055415:Bone Morphogenetic Protein 4 / Q000502:physiology*; D002454:Cell Differentiation; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers; D005822:Genetic Vectors; D007150:Immunohistochemistry; D051379:Mice; D032446:Myoblasts / Q000166:cytology*; D010006:Osteoblasts / Q000166:cytology*; D015398:Signal Transduction; D051901:Smad4 Protein / Q000502:physiology*
C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D017931:DNA Primers; D051901:Smad4 Protein; C490810:Smad4 protein, mouse