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

Abstract

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.

The distinct roles of MMP-2 and MMP-9 in acute DSS colitis

“…Taken together, these studies revealed that epithelial-derived MMP-9 is an important mediator in colitis at early stages of disease development whereas MMP-2 exerts protective function preserving intestinal epithelial barrier integrity [36,37]. The colitis-mediating properties of MMP-9, however, were shown to override MMP-2's protective function during colitis [37].…”

“…Studies with bone marrow chimera revealed that MMP-2 and MMP-9 derived from epithelial but not immune cells, mediated colonic inflammation [34,36]. Furthermore, Garg and coworkers could show that besides MMP-2 knockout [36], MMP-2/ MMP-9 double deficient animals [37] also suffered from acute colitis following DSS treatment or Salmonella Typhimurium infection. Taken together, these studies revealed that epithelial-derived MMP-9 is an important mediator in colitis at early stages of disease development whereas MMP-2 exerts protective function preserving intestinal epithelial barrier integrity [36,37].…”

“…Furthermore, Garg and coworkers could show that besides MMP-2 knockout [36], MMP-2/ MMP-9 double deficient animals [37] also suffered from acute colitis following DSS treatment or Salmonella Typhimurium infection. Taken together, these studies revealed that epithelial-derived MMP-9 is an important mediator in colitis at early stages of disease development whereas MMP-2 exerts protective function preserving intestinal epithelial barrier integrity [36,37]. The colitis-mediating properties of MMP-9, however, were shown to override MMP-2's protective function during colitis [37].…”

A chemical enterocolitis model in zebrafish larvae that is dependent on microbiota and responsive to pharmacological agents

“…MMP9 has been identified as a mediator of intestinal damage in colitis models (Garg et al, 2009). In zebrafish larvae exposed to TNBS, an increase in the transcription of mmp9 was observed from 24 hr after exposure, wholemount in situ hybridization analysis of expression demonstrated increased mmp9 expression in epidermal tissues (Supp.…”

Extracellular matrix protein 1 gene rs3737240 single nucleotide polymorphism is associated with ulcerative colitis in Turkish patients

“…It is a fundamental immune regulator in IBD pathogenesis. Mutations that lead to tissue loss in patients with ECM1 SNPs probably increase the tissue injury caused by MMP-9, resulting in an increase in intestinal ulcers and scars in IBD (8). In addition, ECM1 is also associated with cell proliferation, angiogenesis, and differentiation; ECM1 expression has been demonstrated to be increased in metastatic epithelial tumors, such as those in gastric and colorectal cancers (9).…”