Roles of bone morphogenetic protein type I receptors and Smad proteins in osteoblast and chondroblast differentiation.
The biological effects of type I serine/threonine kinase receptors and Smad proteins were examined using an adenovirus-based vector system. Constitutively active forms of bone morphogenetic protein (BMP) type I receptors (BMPR-IA and BMPR-IB; BMPR-I group) and those of activin receptor-like kinase (ALK)-1 and ALK-2 (ALK-1 group) induced alkaline phosphatase activity in C2C12 cells. Receptor-regulated Smads (R-Smads) that act in the BMP pathways, such as Smad1 and Smad5, also induced the alkaline phosphatase activity in C2C12 cells. BMP-6 dramatically enhanced alkaline phosphatase activity induced by Smad1 or Smad5, probably because of the nuclear translocation of R-Smads triggered by the ligand. Inhibitory Smads, i.e., Smad6 and Smad7, repressed the alkaline phosphatase activity induced by BMP-6 or the type I receptors. Chondrogenic differentiation of ATDC5 cells was induced by the receptors of the BMPR-I group but not by those of the ALK-1 group. However, kinase-inactive forms of the receptors of the ALK-1 and BMPR-I groups blocked chondrogenic differentiation. Although R-Smads failed to induce cartilage nodule formation, inhibitory Smads blocked it. Osteoblast differentiation induced by BMPs is thus mediated mainly via the Smad-signaling pathway, whereas chondrogenic differentiation may be transmitted by Smad-dependent and independent pathways.
Fujii
M
M
Department of Biochemistry, The Cancer Institute of the Japanese Foundation for Cancer Research and Research for the Future Program, Tokyo, Japan. fjios@dent.tmd.ac.jp
Takeda
K
K
Imamura
T
T
Aoki
H
H
Sampath
T K
TK
Enomoto
S
S
Kawabata
M
M
Kato
M
M
Ichijo
H
H
Miyazono
K
K
D029404:Activin Receptors; D000256:Adenoviridae / Q000235:genetics; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D052005:Bone Morphogenetic Protein Receptors, Type I; D002454:Cell Differentiation; D002460:Cell Line; D019902:Chondrocytes; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005822:Genetic Vectors; D006651:Histocytochemistry; D051379:Mice; D010006:Osteoblasts; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017978:Receptors, Growth Factor / Q000378:metabolism*; D051785:Smad Proteins; D051898:Smad1 Protein; D051902:Smad5 Protein; D051905:Smad6 Protein; D051906:Smad7 Protein; D015534:Trans-Activators / Q000378:metabolism*
D004268:DNA-Binding Proteins; D010750:Phosphoproteins; D017978:Receptors, Growth Factor; D051785:Smad Proteins; D051898:Smad1 Protein; C497401:Smad1 protein, mouse; D051902:Smad5 Protein; C497798:Smad5 protein, mouse; D051905:Smad6 Protein; C497803:Smad6 protein, mouse; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D015534:Trans-Activators; D017346:Protein Serine-Threonine Kinases; D029404:Activin Receptors; C498212:Bmpr1a protein, mouse; C498215:Bmpr1b protein, mouse; D052005:Bone Morphogenetic Protein Receptors, Type I; D000469:Alkaline Phosphatase