Distinct roles for AF-1 and -2 of ER-alpha in regulation of MMP-13 promoter activity.

Previous studies have indicated that ER-alpha can influence the activity of the MMP-13 promoter. ER-alpha activity is mediated by two separate transcriptional activation domains (AF-1 and AF-2). The present study focused on analyzing the roles of these domains on the activation of the MMP-13 promoter. Transfection of synoviocytes with an ER-alpha construct lacking the C-terminus AF-2 domain led to significant elevation in MMP-13 promoter activity compared to wild type ER-alpha. Progressive deletions in the N-terminal AF-1 domain led to significant losses in MMP-13 promoter activity. MMP-13 promoter mutagenesis indicated that an AP-1 regulatory site was essential for ER-alpha mutant activity. Thus, both AF-1 and AF-2 domains of ER-alpha are required for regulation of MMP-13 promoter activity. As ER variants and ER related proteins have been implicated in bone and joint disorders, these findings provide understanding of the possible role of ER variants in the development of such conditions.