Expression and localisation of matrix metalloproteinases and their natural inhibitors in fistulae of patients with Crohn's disease

Abstract

Background: Fistulae are a troublesome complication of Crohn's disease but little is known of the final effector molecules responsible for matrix degradation. Although matrix metalloproteinases (MMPs) have been strongly implicated in tissue injury in Crohn's disease, their role in fistula formation is unknown. Aim: To determine the expression pattern of MMPs and tissue inhibitors of metalloproteinases (TIMPs) in fistulae of patients with Crohn's disease. Patients and methods: Resected fistula specimens were obtained from patients with Crohn's disease (n = 11) and classified according to the predominant histological features-that is, acute versus chronic inflammation. Patients with fistulae due to other diseases (n = 9) and normal colon (n = 5) served as controls. MMP and TIMP protein expression was measured by single or double labelled immunohistochemistry, and mRNA expression by in situ hybridisation. MMP activity was measured by gelatin zymography. Results: Compared with normal colon, strong MMP-3 expression was consistently observed in fistulae in Crohn's disease, irrespective of the stage of inflammatory activity. MMP-3 transcripts and protein were localised in large mononuclear cells and fibroblasts. MMP-9 transcripts and protein were expressed in granulocytes and only in fistulae with acute inflammation. Staining for MMP-1 and MMP-7 was weak and negative for MMP-10, whereas MMP-2 was equally expressed in normal colon and fistulae. TIMP-1, TIMP-2, and TIMP-3 expression was low in all samples. Similar expression patterns were found in fistulae of the disease control group. Fistulae also expressed active MMP-2 and MMP-9, as measured by gelatin zymography. Conclusion: MMP-3 and MMP-9 are markedly upregulated in intestinal fistulae and may contribute to fistula formation through degradation of the extracellular matrix, irrespective of the underlying disease process.

A role for membrane-bound CD147 in NOD2-mediated recognition of bacterial cytoinvasion

“…The best characterized function of CD147 is production and activation of matrix-metalloproteases (MMPs) and involvement in cell adhesion (Choi et al, 2002;Lim et al, 1998;Schmidt et al, 2006). Remarkably, patients suffering from Crohn disease show enhanced expression levels of MMP1 and MMP9 in colonic tissue, especially in fistulae (Kirkegaard et al, 2004;Stumpf et al, 2005). Further studies will have to clarify if CD147 directly contributes to MMP dysregulation in chronic intestinal inflammation.…”

Selective Ablation of Matrix Metalloproteinase-2 Exacerbates Experimental Colitis: Contrasting Role of Gelatinases in the Pathogenesis of Colitis

“…These authors further showed that fibroblast-derived MMP-2 was required for stromal remodeling that is integral to corneal wound healing. Along with the observations that myofibroblasts are an important source of MMP-2 during intestinal inflammation (19) and are integral to epithelial wound healing, it is likely that MMP-2 may play a role in tissue remodeling that is required for proper wound healing (50,51).…”

“…Although MMPs play important roles in normal tissue remodeling, dysregulated expression has been implicated in several pathological processes, such as arthritis (1,12), atherosclerosis, myocardial infarction (13), colorectal cancer, tumor invasion (14,15), and IBD (4,16). In many acute and chronic inflammatory events such as IBD, MMP levels have been shown to be up-regulated (17)(18)(19)(20)(21)(22)(23).…”

The parasite Entamoeba histolytica exploits the activities of human matrix metalloproteinases to invade colonic tissue

“…Furthermore, we demonstrated that pro-MMP-1 is not directly activated by mature CP-A5; in fact, CP-A5 activates pro-MMP-3, which in turn activates pro-MMP-1. Stromelysin-1 (MMP-3) cleaves proteoglycans, collagen (types II, IX and XI), gelatin, laminin and fibronectin, and has been linked to tissue degradation in pathological situations (such as inflammatory bowel disease and Crohn's disease) in which MMP-3 contributes to ECM degradation 28,29 . In our disease model, MMP-3 was expressed by epithelial cells, suggesting that this enzyme could contribute to extensive desquamation through degradation of the basal membrane, which supports the epithelial cells lining in the colon.…”