Selective regulation of Mmp13 by 1,25(OH)2 D3 , PTH, and Osterix through distal enhancers

The Journal of Steroid Biochemistry and Molecular Biology
Mark B MeyerJ Wesley Pike

Abstract

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 -10, -20, and -30kb 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 -10kb VDR bound enhancer. Rather, the -30kb 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 -10kb enhancer mouse model. Despi...Continue Reading

Citations

Jan 17, 2019·Current Molecular Pharmacology·Anna Boguszewska-CzubaraBarbara Budzyńska
Jan 30, 2018·Journal of Cellular Biochemistry·Li-Ping YangQun Zhao
Feb 28, 2017·The Journal of Clinical Investigation·J Wesley PikeNancy A Benkusky
Mar 5, 2019·F1000Research·David A YoungDavid J Wilkinson
Apr 23, 2021·ELife·Carly V WeissDavid Gokhman

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