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      Matrix Metalloproteinase-9: Its Interplay with Angiogenic Factors in Inflammatory Bowel Diseases

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          Abstract

          Matrix metalloproteinase- (MMP-) 9 is one of the main metalloproteinases reported to be involved in extracellular matrix degradation and recently also in triggering of angiogenic switch in the course of inflammatory bowel diseases (IBD). The goal of our studies was to estimate in one experimental setting the levels of MMP-9 in sera of Crohn's Disease (CD) and ulcerative colitis (UC) patients and to evaluate its possible diagnostic potential in comparison with other biochemical markers and selected proinflammatory and angiogenic factors. The study group included 176 subjects (CD = 64, UC = 85, control = 27). Concentrations of serum MMP-9 were significantly higher in active than inactive forms of IBD, being higher in active UC than in active CD. Both in the case of CD and UC serum MMP-9 positively correlated with disease activity, IL-6 levels, platelet and leukocyte count, midkine, and PDGF-BB, as well as in UC with ESR and in CD with CRP, IL-1, and VEGF-A. Diagnostic accuracy of MMP-9 in distinguishing active UC from active CD was 66%, and displayed higher specificity than CRP (79.0% versus 61.6%, resp.). Evaluation of serum MMP-9 concentrations could aid in differentiation of active UC from active CD. MMP-9 correlated better with inflammatory and angiogenic parameters in CD than in UC.

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          Most cited references49

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          How matrix metalloproteinases regulate cell behavior.

          The matrix metalloproteinases (MMPs) constitute a multigene family of over 25 secreted and cell surface enzymes that process or degrade numerous pericellular substrates. Their targets include other proteinases, proteinase inhibitors, clotting factors, chemotactic molecules, latent growth factors, growth factor-binding proteins, cell surface receptors, cell-cell adhesion molecules, and virtually all structural extracellular matrix proteins. Thus MMPs are able to regulate many biologic processes and are closely regulated themselves. We review recent advances that help to explain how MMPs work, how they are controlled, and how they influence biologic behavior. These advances shed light on how the structure and function of the MMPs are related and on how their transcription, secretion, activation, inhibition, localization, and clearance are controlled. MMPs participate in numerous normal and abnormal processes, and there are new insights into the key substrates and mechanisms responsible for regulating some of these processes in vivo. Our knowledge in the field of MMP biology is rapidly expanding, yet we still do not fully understand how these enzymes regulate most processes of development, homeostasis, and disease.
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            Coated mesalazine (5-aminosalicylic acid) versus sulphasalazine in the treatment of active ulcerative colitis: a randomised trial.

            To assess the safety and efficacy of a preparation of mesalazine (5-aminosalicylic acid) coated with a pH dependent resin (Eudragit L) as compared with sulphasalazine in patients with active mild to moderate ulcerative colitis. Eight week randomised double blind parallel group study. Forty six gastroenterology outpatient clinics in seven countries. Two hundred and twenty patients aged 18-70 who met the following criteria: clinical activity index greater than or equal to 6 and endoscopic index greater than or equal to 4; no concomitant treatment for ulcerative colitis; no hypersensitivity to salicylates or sulphonamides. Of the 164 patients eligible for efficacy analysis, 87 received the coated preparation of mesalazine and 77 sulphasalazine. Most of the remaining patients (28 in each group) were ineligible for the efficacy analysis because of treatment with steroid enemas. All pretrial characteristics were comparable in the two treatment groups. Coated mesalazine (Mesasal) 1.5 g daily or sulphasalazine 3.0 g daily for eight weeks. Compliance monitored by pill counts. Clinical and endoscopic remission. Clinical activity measured by daily diary cards, assessment by investigators, and laboratory findings. Endoscopic evaluation at week 8. After four weeks 50 of 70 patients (71%) taking coated mesalazine and 38 of 58 (66%) taking sulphasalazine had achieved remission of their disease by eight weeks remission rates were 74% (37/50 patients) and 81% (35/43) in the two treatment groups respectively. Endoscopic remission at eight weeks was recorded in 20 of 41 patients (49%) taking coated mesalazine and 18 of 38 (47%) taking sulphasalazine. There was a higher incidence of adverse events among patients taking sulphasalazine (25/105; 24%) than among those taking coated mesalazine (16/115; 14%). Mesalazine coated with Eudragit L is a safe, logical alternative to sulphasalazine.
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              Matrix metalloproteinases and angiogenesis.

              Matrix metalloproteinases (MMPs) are a family of enzymes that proteolytically degrade various components of the extracellular matrix (ECM). Angiogenesis is the process of forming new blood vessels from existing ones and requires degradation of the vascular basement membrane and remodeling of the ECM in order to allow endothelial cells to migrate and invade into the surrounding tissue. MMPs participate in this remodeling of basement membranes and ECM. However, it has become clear that MMPs contribute more to angiogenesis than just degrading ECM components. Specific MMPs have been shown to enhance angiogenesis by helping to detach pericytes from vessels undergoing angiogenesis, by releasing ECM-bound angiogenic growth factors, by exposing cryptic proangiogenic integrin binding sites in the ECM, by generating promigratory ECM component fragments, and by cleaving endothelial cell-cell adhesions. MMPs can also contribute negatively to angiogenesis through the generation of endogenous angiogenesis inhibitors by proteolytic cleavage of certain collagen chains and plasminogen and by modulating cell receptor signaling by cleaving off their ligand-binding domains. A number of inhibitors of MMPs that show antiangiogenic activity are already in early stages of clinical trials, primarily to treat cancer and cancer-associated angiogenesis. However, because of the multiple effects of MMPs on angiogenesis, careful testing of these MMP inhibitors is necessary to show that these compounds do not actually enhance angiogenesis.
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                Author and article information

                Journal
                Dis Markers
                Dis. Markers
                DM
                Disease Markers
                Hindawi Publishing Corporation
                0278-0240
                1875-8630
                2014
                31 March 2014
                : 2014
                : 643645
                Affiliations
                1Department of Medical Biochemistry, Wroclaw Medical University, Chalubinskiego 10, 50-358 Wroclaw, Poland
                2Department of Gastroenterology and Hepatology, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland
                3Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigla 12, 53-114 Wroclaw, Poland
                Author notes

                Academic Editor: Silvia Persichilli

                Author information
                http://orcid.org/0000-0003-4624-0109
                http://orcid.org/0000-0003-3650-9311
                http://orcid.org/0000-0001-9640-4883
                Article
                10.1155/2014/643645
                3988740
                24803722
                67861fc6-3e5f-4af5-bd9e-512808f07d34
                Copyright © 2014 Malgorzata Matusiewicz et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 23 December 2013
                : 3 March 2014
                Funding
                Funded by: Wroclaw Medical University Research
                Award ID: ST-45, ST-459
                Funded by: Wroclaw Research Center EIT+
                Award ID: POIG 01.01.02-02-003/08-00
                Funded by: European Regional Development Fund
                Categories
                Research Article

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