Matrix metalloproteinases in inflammatory bowel disease: Boon or a bane?

Abstract

Matrix metalloproteinases (MMPs) are a family of Zn(2+)-dependent extracellular matrix (ECM) degrading endopeptidases that share common functional domains, activation mechanisms, and collectively have the capacity to degrade all types of ECM proteins. In addition to playing a central role in ECM turnover, MMPs proteolytically activate or degrade a variety of nonmatrix substrates including chemokines, cytokines, growth factors, and junctional proteins. Thus, they are increasingly recognized as critical players in inflammatory response. Indeed, accumulating data from several studies indicate that they are the predominant proteases involved in the pathogenesis of inflammatory bowel disease (IBD) via their influence on the function and migration of inflammatory cells, mucosal ulceration, as well as matrix deposition and degradation. Some MMPs are constitutively expressed and play a protective role in IBD through their effect on cellular homeostasis, while others are induced during inflammation-mediated tissue damage. This article focuses on the role of the various MMPs in IBD, discussing their physiologic and pathogenetic role in the context of intestinal defense, mucosal inflammatory response, and immune cell-epithelial interaction.

Comparison of Two Chemically-Induced Colitis-Models in Adult Zebrafish, Using Optical Projection Tomography and Novel Transcriptional Markers

“…Matrix metalloproteinases (MMPs), a family of degradative enzymes, are crucial factors in inflammatory conditions in humans [42]. In relation to colitis, MMP-9 isconsidered to be the most important protease and it is distinctly overexpressed in both forms of IBD in humans and rodent models [43] [44] [45].…”

Transepithelial Migration of Neutrophils

“…While MMPs clearly degrade the extracellular matrix (ECM), with nearly every ECM component a potential substrate of MMPs (215), the effects of MMPs on the endothelia and epithelia are less clear. Certain MMPs do appear to play a role in maintaining epithelial integrity (211), in part via proteolytic cleavage of E-cadherin and occludin, leading to tight and adherens junction disassembly (215)(216)(217).…”

“…Certain MMPs do appear to play a role in maintaining epithelial integrity (211), in part via proteolytic cleavage of E-cadherin and occludin, leading to tight and adherens junction disassembly (215)(216)(217). By analogy, endothelial permeability is regulated by MMP degradation of occludin (218) and E-cadherin (219).…”

Matrix metalloproteinase 9-induced increase in intestinal epithelial tight junction permeability contributes to the severity of experimental DSS colitis

“…Matrix metalloproteinases (MMPs) have recently been suggested to play a central role in the pathogenesis of intestinal inflammation in IBD (30,37,41). MMPs are Zn 2ϩ -dependent endopeptidases that degrade the extracellular matrix (ECM) and regulate ECM homeostasis (30,41).…”