Estrogen receptor alpha regulates matrix metalloproteinase-13 promoter activity primarily through the AP-1 transcriptional regulatory site

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-α 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-α 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-α 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-α dependent enhancement of the promoter activity. This enhancement by ER-α 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-α 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.