The molecular biology of matrix metalloproteinases and tissue inhibitors of metalloproteinases in inflammatory bowel diseases

Abstract

Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are thought to be predominant proteases and protease inhibitors involved in the pathogenesis of inflammatory bowel diseases (IBD) through their ability to remodel the extracellular matrix (ECM) in response to inflammatory stimuli and by their immunomodulating effects. An imbalance between MMPs and TIMPs has been linked with acute and chronic inflammation and aberrant tissue remodeling, as seen in IBD. Moreover, recurrent phases of tissue destruction and subsequent tissue repair can cause serious complications in IBD patients such as fistulas and fibrosis. The aims of this review are (i) to summarize current literature on genetic association, mRNA, and protein expression studies with regard to MMPs and TIMPs in IBD patients and various animal models, including those with transgenic and knockout mice; (ii) to compare biochemical and molecular biological data in humans with those obtained in animal model studies and (iii) to critically evaluate and translate how this knowledge may be used in practical terms to understand better the pathophysiology and mechanisms operating in IBD and to apply this for improvement of clinical outcomes at diagnostic, prognostic and therapeutic levels.

Inhibition of gelatinase B/MMP-9 does not attenuate colitis in murine models of inflammatory bowel disease

“…In a subset of MMP and TIMP genes, we found that upregulation of Mmp8 and Mmp10 by DSS was shared between both genotypes, whereas Mmp3 , Mmp9 , Mmp12, Mmp13, Mmp19 and Timp1 were uniquely upregulated in WT mice. The general picture emerging from this extensive gene expression analysis is also in line with our microarray data of IBD patients under anti-tumour necrosis factor treatment35 and points towards the idea that the disease process induces altered expression of several MMPs and TIMPs3, rather than being the result of MMP-9 specifically.…”

“…7a) which has a different immunological mechanism and is more related to CD in humans3. We found that both WT and MMP-9 −/− mice lost significant amounts of body weight after rectal administration of TNBS compared to corresponding control mice that received 50% EtOH (Fig.…”

“…18) and because MMP-8 and MMP-9 are major neutrophil MMPs (refs 3, 4, 5), we evaluated colonic expression levels of specific mRNAs in control and DSS-induced and peptide-treated mice. As expected, mice with acute DSS-induced colitis had significantly increased expression of Mmp3 , Mmp8 and Mmp9 compared to control mice (Fig.…”

“…Therefore, we used two models of chemically induced colitis, namely DSS and TNBS, that are driven by different immunological mechanisms3. The DSS model more closely resembles UC, whereas TNBS is more representative for CD in humans.…”

“…However, up to one third of patients become therapy-resistant and, consequently, new pharmacological targets are needed. Within the matrix metalloproteinase (MMP) family, gelatinase B or MMP-9 is suggested as a novel therapeutic target for the treatment of IBD, because MMP-9 expression is associated with disease development and is reduced by efficient treatment, as recently reviewed3. Moreover, the covalent complex of MMP-9 with neutrophil gelatinase B-associated lipocalin is a serum marker of mucosal healing in UC4 and CD5.…”