BMP2 Differentially Regulates the Expression of Gremlin1 and Gremlin2, the Negative Regulators of BMP Function, During Osteoblast Differentiation
BMP2 Differentially Regulates the Expression of Gremlin1 and Gremlin2, the Negative Regulators of BMP Function, During Osteoblast Differentiation
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DOI：
10.1007/s00223-012-9614-5
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发表时间：
2012-07-01
影响因子：
4.2
通讯作者：
Kamijo, Ryutaro
中科院分区：
文献类型：
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作者：
Suzuki, Dai;Yamada, Atsushi;Kamijo, Ryutaro
骨形态发生蛋白（BMPs）控制许多参与骨形成的基因的表达。基于我们的假设，BMP2刺激调节的基因表达在成骨细胞分化中起关键作用，我们使用DNA微阵列技术对BMP2处理和未处理的C2C12细胞的信使RNA进行全基因组筛选。我们发现，已知的BMP拮抗剂Gremlin1和Gremlin2的表达受BMP2的双向调节。Gremlin1被BMP2下调，而Gremlin2则以时间和剂量依赖的方式上调。消融Gremlin1或Gremlin2可增强BMP2诱导的成骨细胞分化。另一方面，重组Gremlin1抑制bmp2诱导的成骨细胞分化。此外，用Smad4 siRNA和p38 MAPK抑制剂SB203580处理可抑制bmp2诱导的Gremlin2基因表达。BMP2对Gremlin1和Gremlin2基因表达的差异调控可能解释了这些基因在成骨细胞分化过程中的关键功能。
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.