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

Gastroenterology. 2005 Dec;129(6):1991-2008. doi: 10.1053/j.gastro.2005.09.017.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • Dextran Sulfate
  • Matrix Metalloproteinase 9