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- fibrosis
- inflammatory bowel disease
- proteolysis
- matrix metalloproteinases
- tissue inhibitor of metalloproteinase
- ulcerative colitis
- vitronectin receptor
- Crohn’s disease
- fistulae
Broadening our understanding of the role of matrix metalloproteinases in Crohn’s disease
Fistulae are a common complication of Crohn’s disease (CD), and their most common perianal manifestation is present in 14–38% of CD patients in referral populations.1 Despite advances in conservative treatment, fistulae rarely heal, while surgical resection is effective but frequently does not prevent local recurrence or fistulising disease at other sites.1 Remodelling of the extracellular matrix (ECM) is a key event in chronic bowel inflammation,2,3 especially in CD which is characterised by both active fibrogenesis (that is, ECM production and deposition), leading, for example, to stricture formation, and by enhanced fibrolyis (that is, breakdown and removal of ECM), such as occurs in fistula formation. While fibroblasts and myofibroblasts, and to a minor degree endothelial and epithelial cells, produce the intestinal ECM, many more cell types are involved in ECM breakdown by releasing a broad spectrum of enzymes that can degrade essentially every ECM component, such as the various collagens, non-collagenous (glyco-) proteins, glycosaminoglycans, and proteoglycans. The most important of these enzymes are the matrix metalloproteinases (MMPs), a structurally related class of at least 20 zinc dependent proteases.4,5 MMPs are classified according to their primary specificities and structural features into interstitial collagenases (MMP-1, MMP-8, MMP-13, MMP-18), gelatinases (degrading denatured and basement membrane collagens: MMP-2, MMP-9), stromelysins (degrading a broad spectrum of ECM substrates: MMP-3, MMP-7, MMP-10, MMP-11), elastases (MMP-12), and membrane-type (transmembrane) MMPs (with broad substrate specificities: MMP-14, MMP-15, MMP-16, MMP-17, MMP-24, MMP-25).
As uncontrolled MMP activity would virtually lead to dissolution of organs, MMP activity is strictly controlled, not only at the transcriptional and translational levels, but also by the requirement of proteolytic activation of the zymogens and by several protease inhibitors. Proteolytic activation occurs by the plasminogen activator-plasmin cascade and …