Gastroenterology

Gastroenterology

Volume 129, Issue 6, December 2005, Pages 1991-2008
Gastroenterology

Basic–alimentary tract
Targeted Deletion of Metalloproteinase 9 Attenuates Experimental Colitis in Mice: Central Role of Epithelial-Derived MMP

https://doi.org/10.1053/j.gastro.2005.09.017Get rights and content

Background & Aims: There is mounting evidence that matrix metalloproteinases are the predominant proteinases expressed in the gut mucosa during active inflammatory bowel disease. We investigated the role of metalloproteinase 9 (MMP-9), a secreted gelatinase that is consistently up-regulated in both animal models and human inflammatory bowel disease and is associated with disease severity, in the pathogenesis of colitis by using mice containing a targeted deletion of the MMP-9 gene. Methods: Dextran sodium sulfate–induced colitis and Salmonella typhimurium–induced enterocolitis were used as animal models to study colitis. Results: MMP-9 activity and protein expression were absent from normal colonic mucosa but were up-regulated during experimental colitis. MMP-9−/− mice exposed to dextran sodium sulfate or salmonella had a significantly reduced extent and severity of colitis. Immunohistochemical studies showed that MMP-9 was localized to epithelial cells and granulocytes during active colitis. The immune response to systemic administration of Salmonella typhimurium was not affected in MMP-9−/− mice. Neutrophil transmigration studies and bone marrow chimeras showed that neutrophil MMP-9 is neither required for its migration nor sufficient to induce tissue damage during colitis and that epithelial MMP-9 is important for tissue damage. MMP-9 inhibited cell attachment and wound healing in the model intestinal epithelial cell line, Caco2-BBE. Conclusions: Taken together, our data suggest that MMP-9 expressed by epithelial cells may play an important role in the development of colitis by modulating cell–matrix interaction and wound healing. Thus, strategies to inhibit MMP-9 may be of potential therapeutic benefit.

Section snippets

Experimental Animals

The Animal Care Committee of the Emory University, Atlanta, Georgia, approved all procedures performed on animals. In addition, all experiments were conducted in accordance with the Guide for the Care and Use of Laboratory Animals published by the US Public Health Service. MMP-9−/− mice and age- and sex-matched WT littermates were purchased from Jackson Laboratories (Bar Harbor, ME) and bred at our facility. Mice lacking MMP-9 show a normal phenotype except for developmental defects in long

MMP-9 Activity and Expression Are Induced During Experimental Colitis in Mice

We used the DSS-induced colitis model to investigate the level of gelatinolytic enzymes stimulated during the induction of colitis. DSS 3% was administered to WT and MMP-9−/− littermates for 6 days, after which the mice were killed, and colonic tissue was processed to estimate the gelatinolytic activity. To detect the gelatinolytic activity in protein extracts from water- or DSS-treated mice, we performed zymography by using gelatin as a substrate as described in the Materials and Methods

Discussion

To explore the direct evidence for the involvement and role of MMP-9 in the development of experimental colitis, mice with targeted disruption of the MMP-9 gene and WT mice were evaluated for the clinical and histopathologic manifestations of colitis induced by DSS and S typhimurium. Colitis induced by DSS is a well-established preclinical model for studying the pathophysiological aspects of intestinal inflammation, having features of human colitis.45, 53 The results presented here show that WT

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      Increased MMP activity is associated with immune-mediated tissue injury and is found in CD.39 Murine models of dextran sulfate sodium-colitis demonstrate the significance of MMPs, with selected deletion of MMP-9 conferring a protective effect.40-43 Tissue inhibitors of MMP (TIMPs) are the natural inhibitors of MMPs, secreted by MMP-producing cells.44

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    F.E.C., B.W., and M.V.-K. contributed equally to this article.

    Supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK 02802, DK 064644, and DK 06411; an Elsevier Research Initiative Award; a Crohn’s and Colitis Foundation of America Senior Research Award (S.V.S); Grants DK 02831 (D.M), DK 61417 (A.T.G), and HL 68543 (J.R); and Digestive Disease Research Center Grant 5R24DK064399-02.

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