Matrix metalloproteinase-9-mediated tissue injury overrides the protective effect of matrix metalloproteinase-2 during colitis

Pallavi Garg, Matam Vijay Kumar, Lixin Wang, Andrew T. Gewirtz, Didier Merlin, Shanthi V. Sitaraman

Research output: Contribution to journalArticle

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Abstract

Matrixmetalloproteinases (MMP) play an important role in pathogenesis of inflammatory bowel disease (IBD). Two known gelatinases, MMP-2 and MMP-9, are upregulated during IBD. Epithelial-derived MMP-9 is an important mediator of tissue injury in colitis, whereas MMP-2 protects against tissue damage and maintains gut barrier function. It has been suggested that developing strategies to block MMP-9 activity in the gut might be of benefit to IBD. However, given that MMP-2 and MMP-9 are structurally similar, such approaches would also likely inhibit MMP-2. Thus, to gain insight into outcome of inhibiting both MMP-2 and MMP-9, MMP-2 -/-/MMP-9 -/- double knockout mice (dKO) lacking both MMP-2 and MMP-9 were used in this study. Three models of murine colitis were used: dextran sodium sulfate (DSS), Salmonella typhimurium (S.T.), and trinitrobenzene sulfonic acid (TNBS). Our data demonstrate that MMP-2 and MMP-9 activities were highly upregulated in wild-type (WT) mice treated with DSS, S.T., or TNBS whereas dKO mice were resistant to the development of colitis. WT mice had extensive inflammation and tissue damage compared with dKO mice as suggested by histological assessment and myeloperoxidase activity. In conclusion, these results suggest an overriding role of MMP-9 in mediating tissue injury compared with the protective role of MMP-2 in development of colitis. Thus inhibition of MMP-9 may be beneficial in treatment of colitis even if resulting in inhibition of MMP-2.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume296
Issue number2
DOIs
StatePublished - Feb 1 2009

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Matrix Metalloproteinase 2
Matrix Metalloproteinase 9
Colitis
Inflammatory Bowel Diseases
Knockout Mice
Trinitrobenzenes
Wounds and Injuries
Dextran Sulfate
Sulfonic Acids
Salmonella typhimurium
Gelatinases
Peroxidase
Inflammation

All Science Journal Classification (ASJC) codes

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

Cite this

Garg, Pallavi ; Kumar, Matam Vijay ; Wang, Lixin ; Gewirtz, Andrew T. ; Merlin, Didier ; Sitaraman, Shanthi V. / Matrix metalloproteinase-9-mediated tissue injury overrides the protective effect of matrix metalloproteinase-2 during colitis. In: American Journal of Physiology - Gastrointestinal and Liver Physiology. 2009 ; Vol. 296, No. 2.
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abstract = "Matrixmetalloproteinases (MMP) play an important role in pathogenesis of inflammatory bowel disease (IBD). Two known gelatinases, MMP-2 and MMP-9, are upregulated during IBD. Epithelial-derived MMP-9 is an important mediator of tissue injury in colitis, whereas MMP-2 protects against tissue damage and maintains gut barrier function. It has been suggested that developing strategies to block MMP-9 activity in the gut might be of benefit to IBD. However, given that MMP-2 and MMP-9 are structurally similar, such approaches would also likely inhibit MMP-2. Thus, to gain insight into outcome of inhibiting both MMP-2 and MMP-9, MMP-2 -/-/MMP-9 -/- double knockout mice (dKO) lacking both MMP-2 and MMP-9 were used in this study. Three models of murine colitis were used: dextran sodium sulfate (DSS), Salmonella typhimurium (S.T.), and trinitrobenzene sulfonic acid (TNBS). Our data demonstrate that MMP-2 and MMP-9 activities were highly upregulated in wild-type (WT) mice treated with DSS, S.T., or TNBS whereas dKO mice were resistant to the development of colitis. WT mice had extensive inflammation and tissue damage compared with dKO mice as suggested by histological assessment and myeloperoxidase activity. In conclusion, these results suggest an overriding role of MMP-9 in mediating tissue injury compared with the protective role of MMP-2 in development of colitis. Thus inhibition of MMP-9 may be beneficial in treatment of colitis even if resulting in inhibition of MMP-2.",
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Matrix metalloproteinase-9-mediated tissue injury overrides the protective effect of matrix metalloproteinase-2 during colitis. / Garg, Pallavi; Kumar, Matam Vijay; Wang, Lixin; Gewirtz, Andrew T.; Merlin, Didier; Sitaraman, Shanthi V.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 296, No. 2, 01.02.2009.

Research output: Contribution to journalArticle

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