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P097. Analysis of the protease MT1-MMP and its substrates as biomarkers and therapeutic targets in inflammatory bowel disease

A. Koziol1, Á. Pollán1, P. Gonzalo1, N. Nuñez-Andrade1, P.M. Linares2, M.E. Fernández-Contreras2, M. Chaparro2, A. Urzainqui3, F. Sánchez-Madrid3, J.P. Gisbert2, A.G. Arroyo1, 1Centro Nacional de Investigaciones Cardiovasculares (CNIC), Vascular Biology and Inflammation Department, Madrid, Spain, 2Hospital Universitario de La Princesa, IP and CIBERehd, Gastroenterology Unit, Madrid, Spain, 3Hospital Universitario de La Princesa and IP, Immunology Unit, Madrid, Spain

Background

We have recently reported that the protease MT1-MMP is up-regulated in TNFα-activated endothelial cells where it can process substrates normally bound to the extracellular matrix, such as thrombospondin1 (TSP1) and nidogen1 (NID1), inducing their release and thus modulating the angiogenic response. Our aim was to analyse the expression of MT1-MMP and its substrates TSP1 and NID1 as potential biomarkers of inflammatory bowel disease (IBD), a chronic disorder involving inflammation and angiogenesis, in mouse models and human samples.

Methods

A mouse model of dextran sodium sulphate (DSS)-induced colitis was used. Immunostaining (IS) in colon sections was performed to analyse: (i) the angiogenic response with the specific endothelial cell marker CD31/PECAM1, and (ii) the expression of MT1-MMP, TSP1 and NID1, in either control mice, mice treated with 1%DSS (moderate colitis) or 4%DSS (severe colitis). TSP1, NID1 and VEGF levels were also measured by enzyme-linked immunosorbent assay in serum from patients with active ulcerative colitis (UC) or Crohn's disease (CD). The in vivo function of endothelial MT1-MMP in mouse colitis was analysed using recently generated conditional mice with endothelium-specific deletion of MT1-MMP (MT1flox/flox × VECadhERT2-Cre).

Results

Serum levels of the proinflammatory cytokine TNFα and of the proangiogenic factor VEGF-A were upregulated in the DSS-induced colitis model in a dose response manner. This correlated with increased presence of new vessels (CD31/PECAM1+) in the lamina propria (LP) and with MT1-MMP upregulated expression in colonic vascular cells of mice with moderate colitis when compared to either control or mice with severe colitis. Soluble serum levels of TSP1 and NID1 also increased gradually from moderate to severe mouse colitis. In IBD patients, serum levels of TSP-1 and NID1 were significantly higher in UC and CD patients with low disease activity compared to high activity. Preliminary results show that endothelium-specific deletion of MT1-MMP prevents development of DSS-induced colitis in mice.

Conclusion

Vascularization is higher in moderate versus severe colitis in the mouse model. This might correlate with increased expression of MT1-MMP in the LP and increased serum levels of TSP1 and NID1 in 1%DSS-treated mice. Accordingly, serum levels of TSP1 and NID1 (indicative of their processing from the matrix) are significantly increased in patients affected by low active UC and CD when compared with highly active disease. These data support the potential use of TSP1 and NID1 as biomarkers for diagnosis of pre-symptomatic IBD and point to endothelial MT1-MMP as a novel anti-angiogenic target in IBD.