Estrogen Receptor Alpha Regulates Matrix Metalloproteinase-13 Promoter Activity Primarily Through the Ap-1 Transcriptional Regulatory Site.
From: McCaig Centre for Joint Injury and Arthritis Research, Faculty of Medicine, University of Calgary, 3330 Hospital Dr. N W Calgary, Alberta, Canada T2N 4N1.
Biochimica et biophysica acta
- Publish Date: Aug 2006
- ISSN: 0006-3002
- Volume: 1762
- Issue: 8
- Pages: 719-31
- Medium: Print
- Language: English
- Citation (JAMA): Lu Ting, Achari Yamini, Sciore Paul, et al. Estrogen Receptor Alpha Regulates Matrix Metalloproteinase-13 Promoter Activity Primarily Through the Ap-1 Transcriptional Regulatory Site.. Biochim. Biophys. Acta Aug 2006;1762:719-31
Abstract
Many females develop bone diseases such as osteoporosis, and joint diseases such as osteoarthritis after menopause when estrogen levels decline. As estrogen receptors (ER) are present in such tissues, it is possible that the loss of estrogen at menopause influences the expression of enzymes such as members of the MMP family of proteinases to affect bone and connective tissue metabolism. The present study was undertaken to assess a possible relationship between ER-alpha and MMP-13 expression at the promoter level, and to determine how such a relationship could be modulated by ligands such as estrogen. Using a rabbit synovial cell line lacking endogenous ER, a transient transfection system with an ER-alpha construct, and a series of MMP-13 promoter-luciferase constructs of varying lengths and with specific mutations in transcription factor binding sites, it was found that ER-alpha can significantly enhance MMP-13 promoter activity via the AP-1 site, with modulatory influences by the Runx and PEA-3 sites on this ER-alpha dependent enhancement of the promoter activity. This enhancement by ER-alpha was significantly depressed in the presence of 17-ss-estradiol in a dose dependent manner. The influence of tamoxifen and raloxifen on the activity of the ER-alpha was consistent with their known agonist/antagonist activity. These findings indicate that loss of estrogen in vivo could potentially lead to enhanced expression of MMP-13, a proteinase that has been implicated in both osteoporosis and osteoarthritis, and thus contribute to the development and progression of these conditions.
Mesh Headings (Keywords): Animals, Blotting, Western, Cells, Cultured, Collagenases, DNA, Estradiol, Estrogen Receptor alpha, Female, Gene Expression Regulation, Immunohistochemistry, Matrix Metalloproteinase 13, Promoter Regions (Genetics), RNA, Messenger, Rabbits, Selective Estrogen Receptor Modulators, Sequence Deletion, Transcription Factor AP-1, Transfection, Uterus
Check for Full Text / PubMed Unique Identifier (PMID): 16919424
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