Osteoblast-specific transcription factor Osterix increases vitamin D receptor gene expression in osteoblasts.
Osteoblast-specific transcription factor Osterix increases vitamin D receptor gene expression in osteoblasts.
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DOI：
10.1371/journal.pone.0026504
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
MacDonald PN
中科院分区：
文献类型：
--
作者：
Zhang C;Tang W;Li Y;Yang F;Dowd DR;MacDonald PN
Osterix(OSX)是一种成骨细胞特异性转录因子，是间充质干细胞向成骨细胞分化所必需的。在OSX基因敲除的小鼠中，没有发生骨形成。维生素D受体(VDR)是核激素受体超家族的一员，调节靶基因转录，以确保适当控制钙稳态和骨骼发育。在这里，我们提供了几条证据，表明VDR基因是OSX在成骨细胞中转录调控的目标。例如，与野生型头盖骨相比，从OSX缺失胚胎获得的头盖骨VDR表达显著减少。稳定过表达OSX刺激C2C12间充质细胞VDR表达。SiRNA抑制OSX表达导致VDR表达下调。相比之下，VDR缺失小鼠的成骨细胞中OSX水平保持不变。瞬时转基因分析的机械方法表明，OSX以剂量依赖的方式直接激活VDR启动子的1kb片段。为了确定VDR启动子对OSX的响应区域，我们检测了一系列VDR启动子缺失突变体，并将最小的OSX响应区细化到VDR启动子的近120个碱基。另外的点突变被用来鉴定负责OSX激活VDR启动子的两个GC富集区。染色质免疫沉淀分析表明，体内原代成骨细胞中内源性OSX与天然的VDR启动子相关。总而言之，这些数据有力地支持了OSX在VDR基因表达中的直接调节作用。它们进一步为OSX在成骨细胞和成骨细胞分化过程中控制的潜在机制和途径提供了新的见解。
Osterix (Osx) is an osteoblast-specific transcription factor required for osteoblast differentiation from mesenchymal stem cells. In Osx knock-out mice, no bone formation occurs. The vitamin D receptor (VDR) is a member of the nuclear hormone receptor superfamily that regulates target gene transcription to ensure appropriate control of calcium homeostasis and bone development. Here, we provide several lines of evidence that show that the VDR gene is a target for transcriptional regulation by Osx in osteoblasts. For example, calvaria obtained from Osx-null embryos displayed dramatic reductions in VDR expression compared to wild-type calvaria. Stable overexpression of Osx stimulated VDR expression in C2C12 mesenchymal cells. Inhibition of Osx expression by siRNA led to downregulation of VDR. In contrast, Osx levels remained unchanged in osteoblasts in VDR-null mice. Mechanistic approaches using transient transfection assays showed that Osx directly activated a 1 kb fragment of the VDR promoter in a dose-dependent manner. To define the region of the VDR promoter that was responsive to Osx, a series of VDR promoter deletion mutants were examined and the minimal Osx-responsive region was refined to the proximal 120 bp of the VDR promoter. Additional point mutants were used to identify two GC-rich regions that were responsible for VDR promoter activation by Osx. Chromatin immunoprecipitation assays demonstrated that endogenous Osx was associated with the native VDR promoter in primary osteoblasts in vivo. Cumulatively, these data strongly support a direct regulatory role for Osx in VDR gene expression. They further provide new insight into potential mechanisms and pathways that Osx controls in osteoblasts and during the process of osteoblastic cell differentiation.
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影响因子：
5.3
作者：
Kim, Sungtae;Yamazaki, Miwa;Pike, J. Wesley
通讯作者：
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DOI：
10.1073/pnas.94.19.10138
发表时间：
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影响因子：
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