Regulation of matrix metalloproteinase gene expression

Abstract

The metalloproteinases degrade extracellular matrix (ECM) components and activate growth factors, thereby contributing to physiological events (tissue remodeling in pregnancy, wound healing, angiogenesis) and pathological conditions (cancer, arthritis, periodontitis). The intent of this review is to bring together various studies on transcriptional and post-transcriptional control of metalloproteinase expression. Certainly, much information is known as to the cis-elements and corresponding trans-activators regulating expression of these genes. We discuss the fact that a number of the metalloproteinase promoters share common structural features and, therefore, not surprisingly are co-regulated in their expression to some extent. More recently, much effort has been devoted to understanding the role of chromatin in regulating gene expression. While this area has been understudied with respect to matrix metalloproteinase (MMP) regulation, the literature indicates a convincing role for both histone modifications and chromatin-remodeling motors in controlling expression of multiple metalloproteinases. In addition to transcriptional control, mRNA stability and protein translation also contribute to the metalloproteinase product amount. We discuss such studies and how various biological cues, including TGF-beta, regulate the levels of certain collagenases either solely through mRNA stabilization or by jointly targeting transcriptional and post-transcriptional mechanisms. We also discuss the current deficits in our knowledge, concerning tissue-specific expression and why despite elevated amounts/activity of trans-activators targeting MMP promoters in tumor cells, nevertheless, MMP expression is largely restricted to the stromal compartment. Finally, we argue for potential technologies to regulate MMP expression of utility in pathological conditions where these enzymes are aberrantly expressed.