BMP2 differentially regulates the expression of Gremlin1 and Gremlin2, the negative regulators of BMP function, during osteoblast differentiation.
Bone morphogenetic proteins (BMPs) control the expressions of many genes involved in bone formation. On the basis of our hypothesis that BMP2 stimulation-regulated gene expression plays a critical role in osteoblast differentiation, we performed genome-wide screening of messenger RNA from BMP2-treated and -untreated C2C12 cells using a DNA microarray technique. We found that the expressions of Gremlin1 and Gremlin2, which are known BMP antagonists, were bidirectionally regulated by BMP2. Gremlin1 was down-regulated by BMP2, while Gremlin2 was up-regulated in both time- and dose-dependent manners. Ablation of Gremlin1 or Gremlin2 enhanced osteoblast differentiation induced by BMP2. On the other hand, treatment with recombinant Gremlin1 inhibited BMP2-induced osteoblast differentiation. Furthermore, treatment with Smad4 siRNA and the p38 MAPK inhibitor SB203580 suppressed BMP2-induced Gremlin2 gene expression. The differential regulation of Gremlin1 and Gremlin2 gene expressions by BMP2 may explain the critical function of these genes during osteoblast differentiation.
Department of Biochemistry, School of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawa, Tokyo, 142-8555, Japan.
Dai
D
Suzuki
Atsushi
A
Yamada
Ryo
R
Aizawa
Sakie
S
Funato
Takashi
T
Matsumoto
Wataru
W
Suzuki
Masamichi
M
Takami
Yoichi
Y
Miyamoto
Tetsuo
T
Suzawa
Matsuo
M
Yamamoto
Kazuyoshi
K
Baba
Ryutaro
R
Kamijo
D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D016207:Cytokines; D005786:Gene Expression Regulation; D051379:Mice; D010006:Osteoblasts / Q000166:cytology* / Q000378:metabolism; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism
D055396:Bone Morphogenetic Protein 2; D016207:Cytokines; C490088:Grem2 protein, mouse; D011506:Proteins; D034741:RNA, Small Interfering; D051901:Smad4 Protein; C490810:Smad4 protein, mouse