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

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.

• Authors: 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
• Journal: Gastroenterology (Gastroenterology) Vol. 129 Issue 6 Pg. 1991-2008 (Dec 2005) ISSN: 0016-5085 [Print] United States
• PMID: 16344067 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Dextran Sulfate
• Matrix Metalloproteinase 9

Topics

• Animals
• Cell Movement
• Colitis (chemically induced, metabolism, pathology)
• Dextran Sulfate (toxicity)
• Epithelial Cells (cytology, metabolism)
• Female
• Gene Deletion
• Humans
• Inflammatory Bowel Diseases (metabolism, pathology)
• Intestinal Mucosa (cytology, metabolism, pathology)
• Male
• Matrix Metalloproteinase 9 (genetics, metabolism)
• Mice
• Mice, Knockout
• Neutrophils (cytology, metabolism)
• Random Allocation
• Salmonella Infections (immunology, pathology)
• Sepsis (immunology, pathology)
• Wound Healing