Targeted deletion of metalloproteinase 9 attenuates experimental colitis in mice: Central role of epithelial-derived MMP

Florencia E. Castaneda, Baljit Walia, Matam Vijay-Kumar, Neal R. Patel, Susanne Roser, Vasantha L. Kolachala, Mauricio Rojas, Lixin Wang, Gabriela Oprea, Pallavi Garg, Andrew T. Gewirtz, Jesse Roman, Didier Merlin, Shanthi V. Sitaraman

Research output: Contribution to journalArticlepeer-review

185 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1991-2008
Number of pages18
JournalGastroenterology
Volume129
Issue number6
DOIs
StatePublished - Dec 2005

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology

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