Anupama Ravi

Matrix metalloproteinases in inflammatory bowel disease: boon or a bane?

Abstract Matrix metalloproteinases (MMPs) are a family of Zn2+‐dependent extracellular matrix (ECM) degrading endopeptidases that share common functional domains, activation mechanisms, and collectively have the capacity to degrade all types of ECM proteins. In addition to playing a central role in ECM turnover, MMPs proteolytically activate or degrade a variety of nonmatrix substrates including chemokines, cytokines, growth factors, and junctional proteins. Thus, they are increasingly recognized as critical players in inflammatory response. Indeed, accumulating data from several studies indicate that they are the predominant proteases involved in the pathogenesis of inflammatory bowel disease (IBD) via their influence on the function and migration of inflammatory cells, mucosal ulceration, as well as matrix deposition and degradation. Some MMPs are constitutively expressed and play a protective role in IBD through their effect on cellular homeostasis, while others are induced during inflammation‐mediated tissue damage. This article focuses on the role of the various MMPs in IBD, discussing their physiologic and pathogenetic role in the context of intestinal defense, mucosal inflammatory response, and immune cell‐epithelial interaction. (Inflamm Bowel Dis 2007;13:97–107)

Selective Ablation of Matrix Metalloproteinase-2 Exacerbates Experimental Colitis: Contrasting Role of Gelatinases in the Pathogenesis of Colitis

The matrix metalloproteinases (MMPs), MMP-2 and MMP-9, share structural and substrate similarities and are up-regulated during human as well as animal models of inflammatory bowel disease. We recently demonstrated that epithelial-derived MMP-9 is an important mediator of inflammation and tissue damage in colitis. In this study, we examined the role of MMP-2 in acute colitis. Colitis was induced using two models, administration of dextran sodium sulfate (DSS) and Salmonella enterica subsp. serovar Typhimurium (S.T.). Bone marrow chimeras were performed using bone marrow cells from wild-type (WT) and MMP-2−/− mice. Colitis was evaluated by clinical symptoms, myeloperoxidase assay, and histology. MMP-2 protein expression and activity were up-regulated in WT mice treated with DSS or S.T. MMP-2−/− mice were highly susceptible to the development of colitis induced by DSS (or S.T.) compared with WT. During inflammation, MMP-2 expression was increased in epithelial cells as well as in the infiltrating immune cells. Bone marrow chimera demonstrated that mucosa-derived MMP-2 was required for its protective effects toward colitis. Furthermore, we demonstrate that severe colitis in MMP-2−/− is not due to a compensatory increase in MMP-9. Finally, we show that MMP-2 regulates epithelial barrier function. In contrast to MMP-9, mucosa-derived MMP-2 may be a critical host factor that is involved in the prevention or cessation of the host response to luminal pathogens or toxins, an important aspect of healing and tissue resolution. Together, our data suggest that a critical balance between the two gelatinases determines the outcome of inflammatory response during acute colitis.

M2004 Deletion of Matrix Metalloproteinase-9 (MMP-9) Increases the Susceptibility for Colon Cancer

tumor progression and the development of inflammation. Inflammation and tumor grade were evaluated histologically and colonic levels of IL-12p40 and TNFαmRNAwere measured by real-time PCR. Nuclear β-catenin levels and NF-kB phosphorylation were determined by immunohistochemistry. Results: AOM-treated (6 weekly injections) IL-10-/mice developed colitis and displayed highly penetrant tumor formation under SPF conditions, while WT mice showed no evidence of intestinal inflammation and had minimal tumor formation. AOM-treated IL10-/mice showed a dramatic increase in colon tumor multiplicity and progression compared to WT mice. Tumor multiplicity increased 20-fold while progression from low to high-grade/invasive carcinoma increased by ~70% in IL10-/compared to WT mice. These tumors showed increased nuclear β-catenin accumulation and the presence of phosphorylated RelA. B. vulgatus mono-associated IL10-/mice failed to develop significant intestinal inflammation and showed greatly reduced tumor formation. AOM-treated IL10-/; MyD88-/mice showed reduced colonic expression of TNFα and IL12p40 mRNA and were devoid of neoplastic lesions compared to AOM-treated IL10-/mice. Conclusions: Bacterial-induced intestinal inflammation correlates with the progression of colon cancer in AOM-treated IL-10-/mice. The TLR/MyD88 signaling pathway is essential for the development of CAC.