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Selective Ablation of Matrix Metalloproteinase-2 Exacerbates Experimental Colitis: Contrasting Role of Gelatinases in the Pathogenesis of Colitis¹

Pallavi Garg^*, Mauricio Rojas, Anupama Ravi^*, Katrina Bockbrader^*, Steven Epstein^*, Matam Vijay-Kumar, Andrew T. Gewirtz, Didier Merlin^* and Shanthi V. Sitaraman^2,*,

^* Division of Digestive Diseases, Emory University, Atlanta, GA 30322; Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Emory University, Atlanta, GA 30322; and Department of Pathology, Emory University, Atlanta, GA 30322

The matrix metalloproteinases (MMPs), MMP-2 and MMP-9, share structural and substrate similarities and are up-regulated during human as well as animal models of inflammatory bowel disease. We recently demonstrated that epithelial-derived MMP-9 is an important mediator of inflammation and tissue damage in colitis. In this study, we examined the role of MMP-2 in acute colitis. Colitis was induced using two models, administration of dextran sodium sulfate (DSS) and Salmonella enterica subsp. serovar Typhimurium (S.T.). Bone marrow chimeras were performed using bone marrow cells from wild-type (WT) and MMP-2^–/– mice. Colitis was evaluated by clinical symptoms, myeloperoxidase assay, and histology. MMP-2 protein expression and activity were up-regulated in WT mice treated with DSS or S.T. MMP-2^–/– mice were highly susceptible to the development of colitis induced by DSS (or S.T.) compared with WT. During inflammation, MMP-2 expression was increased in epithelial cells as well as in the infiltrating immune cells. Bone marrow chimera demonstrated that mucosa-derived MMP-2 was required for its protective effects toward colitis. Furthermore, we demonstrate that severe colitis in MMP-2^–/– is not due to a compensatory increase in MMP-9. Finally, we show that MMP-2 regulates epithelial barrier function. In contrast to MMP-9, mucosa-derived MMP-2 may be a critical host factor that is involved in the prevention or cessation of the host response to luminal pathogens or toxins, an important aspect of healing and tissue resolution. Together, our data suggest that a critical balance between the two gelatinases determines the outcome of inflammatory response during acute colitis.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK06411, Crohn’s and Colitis Foundation of America Senior Research Award and Elseivier Research Initiative Award (to S.V.S.), National Institute of Diabetes and Digestive and Kidney Diseases Grant DK061941 and DK071594 (to D.M.), and Digestive Disease Research Center Grant 5R24DK064399-02.

² Address correspondence and reprint requests to Dr. Shanthi V. Sitaraman, Division of Digestive Diseases, Room 201-F, 615 Michael Street, Whitehead Research Building, Emory University, Atlanta, GA 30322. E-mail address: ssitar2{at}emory.edu

³ Abbreviations used in this paper: IBD, inflammatory bowel disease; DSS, dextran sodium sulfate; MMP, matrix metalloproteinase; MPO, myeloperoxidase; S.T., Salmonella enterica subsp. serovar Typhimurium; TIMP, tissue inhibitor of metalloproteinase; WT, wild type.

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