Sox9 directly promotes Bapx1 gene expression to repress Runx2 in chondrocytes.
Sox9 directly promotes Bapx1 gene expression to repress Runx2 in chondrocytes.
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DOI：
10.1016/j.yexcr.2009.03.008
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发表时间：
2009-08-01
影响因子：
3.7
通讯作者：
Asahara H
中科院分区：
文献类型：
--
作者：
Yamashita S;Andoh M;Ueno-Kudoh H;Sato T;Miyaki S;Asahara H
转录因子Sry相关的高迁移率族（HMG）盒包含基因9（Sox 9），通过启动软骨形成和防止随后的成熟过程（称为软骨细胞肥大）在软骨发育中起着关键作用。Sox 9对晚期软骨形成的这种抑制机制部分来自于对肥大软骨细胞分化的主要激活因子Runt相关转录因子2（Runx 2）的抑制。然而，Sox 9调节晚期软骨形成的确切机制知之甚少。在本研究中，转录抑制脊椎动物同源果蝇风笛（Bapx1）被发现是一个直接的目标，Sox 9的抑制软骨细胞中的Runx2表达。我们确定了一个关键的Sox9响应区域的Bapx1启动子通过荧光素酶报告分析。染色质免疫沉淀和电泳迁移率变动分析表明，Sox 9物理绑定到该地区的Bapx1启动子。与Bapx 1和Sox 9通过调节Runx 2表达而充当软骨细胞肥大负调节因子的观点一致，软骨细胞中shRNA瞬时敲除Sox 9或Bapx 1表达增加了Runx 2的表达，以及晚期软骨形成标志物Col10a1的表达。此外，虽然Sox 9的过表达降低了Runx2和Col10a1的表达，但同时瞬时敲低Bapx 1则降低了Sox 9的过表达效应。我们的研究结果表明，由Bapx1调节的分子途径将软骨形成中的两个主要调节因子Sox9和Runx2联系起来，以协调骨骼的形成。
The transcription factor, Sry-related High Mobility Group (HMG) box containing gene 9 (Sox9), plays a critical role in cartilage development by initiating chondrogenesis and preventing the subsequent maturation process called chondrocyte hypertrophy. This suppression mechanism by Sox9 on late-stage chondrogenesis partially results from the inhibition of Runt-related transcription factor 2 (Runx2), the main activator of hypertrophic chondrocyte differentiation. However, the precise mechanism by which Sox9 regulates late chondrogenesis is poorly understood. In the present study, the transcriptional repressor vertebrate homolog of Drosophila bagpipe (Bapx1) was found to be a direct target of Sox9 for repression of Runx2 expression in chondrocytes. We identified a critical Sox9 responsive region in the Bapx1 promoter via a luciferase reporter assay. Analysis by chromatin immunoprecipitation and electrophoretic mobility shift assays indicated that Sox9 physically bound to this region of the Bapx1 promoter. Consistent with the notion that Bapx1 and Sox9 act as negative regulators of chondrocyte hypertrophy by regulating Runx2 expression, transient knockdown of Sox9 or Bapx1 expression by shRNA in chondrocytes increased Runx2 expression, as well as expression of the late chondrogenesis marker, Col10a1. Furthermore, while over-expression of Sox9 decreased Runx2 and Col10a1 expressions, simultaneous transient knockdown of Bapx1 diminished that Sox9 over-expressing effect. Our findings reveal that the molecular pathway modulated by Bapx1 links two major regulators in chondrogenesis, Sox9 and Runx2, to coordinate skeletal formation.
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影响因子：
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