1,25-(OH)2-vitamin D3 suppresses the bone-related Runx2/Cbfa1 gene promoter
1,25-(OH)2-vitamin D3 suppresses the bone-related Runx2/Cbfa1 gene promoter
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DOI：
10.1006/excr.2002.5474
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发表时间：
2002-04-01
影响因子：
3.7
通讯作者：
van Wijnen, AJ
中科院分区：
文献类型：
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作者：
Drissi, H;Pouliot, A;van Wijnen, AJ
类固醇激素1，25-（OH）（2）-维生素D3（VD 3）通过激活或抑制许多骨表型基因的转录来调节成骨细胞分化。我们讨论了VD 3是否也通过控制体内骨形成的关键调节因子Runx 2/Cbfa 1的活性来影响骨生成。我们的数据显示，Runx 2的表达在24小时内在MC 3 T3和ROS 17/2.8中被VD 3下调，但在缺乏功能性维生素D受体（VDR）的ROS 24.1细胞中没有下调。瞬时转染试验表明，最初的0.6 kb的骨相关的大鼠和小鼠Runx 2启动子都表现出50%的启动子活性降低，在成骨细胞中响应VD 3。此外，VD 3抑制ROS 24.1细胞中的Runx 2转录仅在VDR的强制表达后。用抗体和寡核苷酸竞争实验进行的凝胶迁移率变动测定表明，近端启动子序列（-92至-16）含有结合VDR/类维生素A X受体异二聚体的功能性VD 3响应元件（VDRE）。该VDRE的突变完全消除了Runx 2启动子对VD 3处理的响应性。这些研究共同确定Runx 2表达受VD 3调节。这种VD 3介导的Runx 2活性抑制在骨形成期间提供了组织特异性和类固醇激素依赖性基因控制之间的调节偶联。(C)2002 Elsevier Science（美国）。
The steroid hormone 1,25-(OH)(2)-vitamin D3 (VD3) regulates osteoblast differentiation by either activating or repressing transcription of numerous bone phenotypic genes. We addressed whether VD3 also influences osteogenesis by controlling activity of the runt-related transcription factor Runx2/Cbfa1, a key regulator of bone formation in vivo. Our data showed that expression of Runx2 was downregulated by VD3 within 24 h in MC3T3 and ROS 17/2.8, but not in ROS 24.1 cells, which lack a functional vitamin D receptor (VDR). Transient transfection assays showed that the initial 0.6 kb of the bone-related rat and mouse Runx2 promoters both exhibited a 50% reduction of promoter activity in response to VD3 in osteoblastic cells. Furthermore, VD3 inhibited Runx2 transcription in ROS 24.1 cells only upon forced expression of the VDR. Gel mobility shift assays with antibodies and oligonucleotide competition experiments demonstrated that proximal promoter sequences (-92 to -16) contain a functional VD3-responsive element (VDRE) that binds a VDR/retinoid X receptor heterodimer. Mutation of this VDRE completely abolished responsiveness of the Runx2 promoter to VD3 treatment. Together these studies establish that Runx2 expression is regulated by VD3. This VD3-mediated suppression of Runx2 activity provides regulatory coupling between tissue-specific and steroid hormone-dependent control of genes during bone formation. (C) 2002 Elsevier Science (USA).