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.
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.
Junya
J
Nojima
Divisions of Pathophysiology, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241.
Kazuhiro
K
Kanomata
Department of Biochemistry, School of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-5555.
Yumi
Y
Takada
Divisions of Pathophysiology, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241.
Toru
T
Fukuda
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.
Shoichiro
S
Kokabu
Divisions of Pathophysiology, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241.
Satoshi
S
Ohte
Department of Biochemistry, School of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-5555.
Takatora
T
Takada
Divisions of Experimental Animal Laboratory, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241.
Tohru
T
Tsukui
Division of Morphogenesis, Department of Developmental Biology, National Institute for Basic Biology, 38 Nishigonaka, Myodaiji, Okazaki, Aichi 444-8585, Japan.
Takamasa S
TS
Yamamoto
Divisions of Pathophysiology, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241.
Hiroki
H
Sasanuma
Divisions of Pathophysiology, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241.
Katsumi
K
Yoneyama
Division of Morphogenesis, Department of Developmental Biology, National Institute for Basic Biology, 38 Nishigonaka, Myodaiji, Okazaki, Aichi 444-8585, Japan.
Naoto
N
Ueno
Divisions of Functional Genomics and System Research, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241.
Yasushi
Y
Okazaki
Department of Biochemistry, School of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-5555.
Ryutaro
R
Kamijo
Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Saitama Medical University, 38 Moro Hongo, Moroyama-machi, Iruma-gun, Saitama 350-0495.
Tetsuya
T
Yoda
Divisions of Pathophysiology, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241. Electronic address: katagiri@saitama-med.ac.jp.
Takenobu
T
Katagiri
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