Matrix metalloproteinase-9-mediated tissue injury overrides the protective effect of matrix metalloproteinase-2 during colitis.
Matrix metalloproteinases (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.
Garg
Pallavi
P
Division of Digestive Diseases, Emory University, Atlanta, GA 30322, USA.
Vijay-Kumar
Matam
M
Wang
Lixin
L
Gewirtz
Andrew T
AT
Merlin
Didier
D
Sitaraman
Shanthi V
SV
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D003092:Colitis / Q000139:chemically induced / Q000201:enzymology / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control*; D003106:Colon / Q000187:drug effects / Q000201:enzymology* / Q000382:microbiology / Q000473:pathology; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D015195:Drug Design; D005260:Female; D005765:Gastrointestinal Agents / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000201:enzymology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011480:Protease Inhibitors / Q000494:pharmacology; D012486:Salmonella typhimurium / Q000472:pathogenicity; D014302:Trinitrobenzenesulfonic Acid
D000893:Anti-Inflammatory Agents; D005765:Gastrointestinal Agents; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D014302:Trinitrobenzenesulfonic Acid; D016264:Dextran Sulfate; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse