Selective regulation of Mmp13 by 1,25(OH)2D3, PTH, and Osterix through distal enhancers.
Selective regulation of Mmp13 by 1,25(OH)2D3, PTH, and Osterix through distal enhancers.
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1,25(OH)2D3、PTH 和 Osterix 通过远端增强子选择性调节 Mmp13。
DOI：
10.1016/j.jsbmb.2015.09.001
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Pike,JWesley
中科院分区：
文献类型：
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作者：
Meyer,MarkB;Benkusky,NancyA;Onal,Melda;Pike,JWesley
基质金属蛋白酶13（MMP 13，胶原酶-3）是软骨细胞和成骨细胞成熟的重要组成部分，在许多疾病状态中异常表达。在转录水平上，Mmp 13受多种生长因子和激素的调控。最值得注意的是，Mmp 13受维生素D激素（1，25（OH）2D 3），甲状旁腺激素（PTH）和几种细胞因子的调节。这些活动分别通过转录因子VDR、RUNX 2、FOS、JUN和Osterix（OSX）的参与而发生。最近，我们发现Mmp 13受转录起始位点上游-10、-20和-30 kb的远端元件调控。这些增强子，沿着来自启动子近端区域的微小贡献，负责配体诱导的，最引人注目的是，Mmp 13基因调控的基础活性。在这里，我们发现PTH和OSX的作用不是通过−10 kb VDR结合增强子发生的。相反，-30 kb的RUNX 2结合增强子和启动子近端区域是活性所必需的。通过RUNX 2的缺失和OSX在细胞中的过表达，我们发现OSX在Mmp 13的调节中具有特定的作用。最后，我们创建了一个体内CRISPR缺失的-10 kb增强子小鼠模型。尽管骨密度和生长正常，但它们不能响应1，25（OH）2D 3上调Mmp 13。这些数据与通过UAMS成骨细胞培养获得的数据一致，并进一步确定了远端增强子在Mmp 13调节中的特定作用。
Matrix metalloproteinase 13 (MMP13,collagenase-3) is a vital component for chondrocyte and osteoblast maturation, and is aberrantly expressed in numerous disease states. At the transcriptional level,Mmp13is controlled by many different growth factors and hormones. Most notably,Mmp13is regulated by the vitamin D hormone (1,25(OH)2D3), parathyroid hormone (PTH), and several cytokines. These activities occur through participation by the transcription factors VDR, RUNX2, FOS, JUN, and Osterix (OSX), respectively. Recently, we discovered thatMmp13is regulated by elements quite distal to the transcriptional start site −10, −20, and −30 kb upstream. These enhancers, along with minor contributions from the region proximal to the promoter, are responsible for the ligand inducible and, most strikingly, the basal activities ofMmp13gene regulation. Here, we found that the actions of PTH and OSX do not occur through the −10 kb VDR bound enhancer. Rather, the −30 kb RUNX2 bound enhancer and the promoter proximal regions were essential for activity. Through RUNX2 deletion and OSX overexpression in cells, we showed a specific role for OSX inMmp13regulation. Finally, we created an in vivo CRISPR deleted −10 kb enhancer mouse model. Despite normal bone density and growth, they fail to up-regulateMmp13in response to 1,25(OH)2D3. These data are consistent with those obtained through UAMS osteoblast cell culture and further define the specific roles of distal enhancers in the regulation ofMmp13.