کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
5513256 | 1540984 | 2016 | 7 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: ReviewSelective regulation of Mmp13 by 1,25(OH)2D3, PTH, and Osterix through distal enhancers ReviewSelective regulation of Mmp13 by 1,25(OH)2D3, PTH, and Osterix through distal enhancers](/preview/png/5513256.png)
- Mmp13 is regulated by coordination of three distinct distal enhancers at â10, â20, and â30Â kb.
- PTH utilizes the promoter proximal region for activation of Mmp13.
- Osterix binds to and regulates Mmp13 through the â30Â kb, â20Â kb and promoter proximal regions.
- CRISPR deletion of the â10Â kb enhancer in mice leads to a loss of Mmp13 induction by 1,25(OH)2D3.
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, Mmp13 is controlled by many different growth factors and hormones. Most notably, Mmp13 is 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 that Mmp13 is regulated by elements quite distal to the transcriptional start site â10, â20, and â30Â 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 of Mmp13 gene regulation. Here, we found that the actions of PTH and OSX do not occur through the â10Â kb VDR bound enhancer. Rather, the â30Â 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 in Mmp13 regulation. Finally, we created an in vivo CRISPR deleted â10Â kb enhancer mouse model. Despite normal bone density and growth, they fail to up-regulate Mmp13 in 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 of Mmp13.
Journal: The Journal of Steroid Biochemistry and Molecular Biology - Volume 164, November 2016, Pages 258-264