Matrix metalloproteinases in inflammatory bowel disease : expression, regulation and clinical relevance

Crohn__s disease (CD) is characterized by chronic, patchy, transmural inflammation of the entire gastrointestinal tract, while ulcerative colitis (UC) is manifested by chronic, continuous, superficial inflammation of the colon. Matrix metalloproteinases (MMPs) constitute a family of matrix degrading zinc and calcium-activated neutral endoproteinases, implicated in a wide range of biological processes. We found a marked upregulation of MMP-1, -2, -3 and -9 relative to their natural inhibitors, i.e., tissue inhibitors of metalloproteinases (TIMP) -1 and/or -2, in inflamed mucosa of IBD patients, paralleled by an increase in net MMP activity. Administration of TNF-alpha neutralizing antibody infliximab_ decreased MMP-1, -3 and -9 expression by cultured intestinal IBD explants and serum MMP-9 levels in CD patients, while MMP-2 levels remained almost the same. These observations suggest diverse regulator y pathways for the MMPs examined and a mechanistic pathway for infliximab_ in the treatment of CD. The T allele at TIMP-1 SNP locus +372 T/C, downregulating TIMP-1, appeared to enhance CD susceptibility and worsen prognosis of these patients. Ultimately, these studies might give rationale for the development of novel therapeutic drugs in IBD, based on the inhibition or activation of one or more members of the matrix metalloproteinases family.UBL - phd migration 201