The zinc finger transcription factor Gli2 mediates bone morphogenetic protein 2 expression in osteoblasts in response to hedgehog signaling
The zinc finger transcription factor Gli2 mediates bone morphogenetic protein 2 expression in osteoblasts in response to hedgehog signaling
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DOI：
10.1128/mcb.02214-05
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发表时间：
2006-08-01
影响因子：
5.3
通讯作者：
Mundy, Gregory R.
中科院分区：
文献类型：
--
作者：
Zhao, Ming;Qiao, Mei;Mundy, Gregory R.
骨形态发生蛋白2（BMP-2）在成骨细胞功能中起着关键作用。在果蝇中，介导hedgehog信号传导的中断肘（Cubitus interruptus，G）调节哺乳动物BMP-2的直系同源物dpp的基因表达。转录因子Gli 2（一种Ci的哺乳动物同源物）的突变导致小鼠严重的骨骼异常。我们假设Gli 2调节BMP-2基因转录，从而调节成骨细胞分化。在本研究中，我们发现，Gli 2的过表达增强BMP-2启动子的活性和mRNA的表达在成骨细胞前体细胞。相反，通过Gli 2小干扰RNA敲低Gli 2表达或Gli 2基因的基因切除导致成骨细胞中BMP-2基因表达的显著抑制。启动子分析，包括染色质免疫沉淀和电泳迁移率变动分析，提供了直接的证据表明，Gli 2物理相互作用的BMP-2启动子。功能研究表明，Gli 2是成骨细胞以BMP-2依赖的方式成熟所必需的。最后，Sonic hedgehog（Shh）刺激BMP-2启动子活性和成骨细胞分化，Shh的作用由Gli 2介导。总之，这些结果表明，Gli 2介导成骨细胞中的hedgehog信号传导，并且是BMP-2基因表达的有力激活剂，而BMP-2基因表达反过来又是正常成骨细胞分化所需的。
Bone morphogenetic protein 2 (BMP-2) plays a critical role in osteoblast function. In Drosophila, Cubitus interruptus (G), which mediates hedgehog signaling, regulates gene expression of dpp, the ortholog of mammalian BMP-2. Null mutation of the transcription factor Gli2, a mammalian homolog of Ci, results in severe skeletal abnormalities in mice. We hypothesize that Gli2 regulates BMP-2 gene transcription and thus osteoblast differentiation. In the present study, we show that overexpression of Gli2 enhances BMP-2 promoter activity and mRNA expression in osteoblast precursor cells. In contrast, knocking down Gli2 expression by Gli2 small interfering RNA or genetic ablation of the Gli2 gene results in significant inhibition of BMP-2 gene expression in osteoblasts. Promoter analyses, including chromatin immunoprecipitation and electrophoretic mobility shift assays, provided direct evidence that Gli2 physically interacts with the BMP-2 promoter. Functional studies showed that Gli2 is required for osteoblast maturation in a BMP-2-dependent manner. Finally, Sonic hedgehog (Shh) stimulates BMP-2 promoter activity and osteoblast differentiation, and the effects of Shh are mediated by Gli2. Taken together, these results indicate that Gli2 mediates hedgehog signaling in osteoblasts and is a powerful activator of BMP-2 gene expression, which is required in turn for normal osteoblast differentiation.