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      The synthetic hydroxyproline-containing collagen analogue (Gly-Pro-Hyp) 10 promotes enzymatic activity of matrixmetalloproteinase-2 in vitro

      1 , 4 , * , 1 , 1 , 2 , 1 , 3

      European Journal of Microbiology and Immunology

      Akadémiai Kiadó, co-published with Springer Science+Business Media B.V., Formerly Kluwer Academic Publishers B.V.

      (GPO)10 , extracellular matrix, in vitro , matrixmetalloproteinase, proMMP-2, gelatinases, enzymatic activation, HT1080, hepatic stellate cellss, DMEM, Dulbecco's Modified Eagle's Medium, DQ-gelatin, dye-quenched gelatin, DSS, dextran sulfate sodium, ECM, extracellular matrix, FCS, fetal calf serum, GAP, H-Gly-Ala-Cys-(Gly-Ala-Pro)5-Gly-Phe-Hyp-Gly-Glu-Arg-(Gly-Ala-Pro)5-NH2 , (GPO)10, H-Gly-Cys-Hyp-(Gly-Pro-Hyp)10-Gly-Cys-Hyp-Gly-NH2 , HSC, hepatic stellate cell, HT1080, human fibrosarcoma cell line, MMP, matrixmetalloproteinase, PBS, phosphate buffered saline, PDGF-BB, platelet-derived growth factor subunit B, PI3-K, phosphoinositide 3-kinase

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          Abstract

          Diseases such as liver fibrosis and intestinal inflammation are characterized by accumulated components of the extracellular matrix (ECM). Given that fibrillar collagen structures were shown to serve as storage site for inactive proforms of matrixmetalloproteinases (MMPs), modulating this MMP-collagen interaction might offer a rational interventional (therapeutic) approach to enhance degradation of accumulated ECM. The synthetic triple helical collagen analogue (Gly-Pro-Hyp) 10 — (GPO) 10 — was shown to trigger release and enzymatic activation of collagen sequestered proMMP-2. In the presented study, we, for the first time, investigated how MMP-(GPO) 10 interaction impacts cellular responses in vitro. We found that recombinant proMMP-2 induced proliferation of hepatic stellate cells (HSC), which was enhanced after addition of (GPO) 10 reaching comparable levels following incubation with fully activated MMP-2. In addition, (GPO) 10 induced HSC migration similar to the platelet-derived growth factor subunit-B. Further, the MMP-2-dependent invasion of HT1080 fibrosarcoma cells through an ECM membrane was enhanced after addition of (GPO) 10. Since cellular proliferation and migration concomitant with matrix degradation is stimulated, we conclude that the MMP-(GPO) 10 interaction also functions in a physiological environment. Thus, a potential therapeutic effect of (GPO) 10 should be further tested in animal models for MMP-associated diseases such as colitis or fibrosis.

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          Most cited references 22

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          Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting.

          Matrix metalloproteinases (MMPs) consist of a multigene family of zinc-dependent extracellular matrix (ECM) remodeling endopeptidases implicated in pathological processes, such as carcinogenesis. In this regard, their activity plays a pivotal role in tumor growth and the multistep processes of invasion and metastasis, including proteolytic degradation of ECM, alteration of the cell-cell and cell-ECM interactions, migration and angiogenesis. The underlying premise of the current minireview is that MMPs are able to proteolytically process substrates in the extracellular milieu and, in so doing, promote tumor progression. However, certain members of the MMP family exert contradicting roles at different stages during cancer progression, depending among other factors on the tumor stage, tumor site, enzyme localization and substrate profile. MMPs are therefore amenable to therapeutic intervention by synthetic and natural inhibitors, providing perspectives for future studies. Multiple therapeutic agents, called matrix metalloproteinase inhibitors (MMPIs) have been developed to target MMPs, attempting to control their enzymatic activity. Even though clinical trials with these compounds do not show the expected results in most cases, the field of MMPIs is ongoing. This minireview critically evaluates the role of MMPs in relation to cancer progression, and highlights the challenges, as well as future prospects, for the design, development and efficacy of MMPIs. © 2010 The Authors Journal compilation © 2010 FEBS.
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            Extracellular matrix remodelling: the role of matrix metalloproteinases.

            Matrix metalloproteinases (MMPs) are a growing family of metalloendopeptidases that cleave the protein components of the extracellular matrix and thereby play a central role in tissue remodelling. For many years following their discovery, MMPs were believed to function primarily as regulators of ECM composition and to facilitate cell migration simply by removing barriers such as collagen. It is becoming increasingly clear, however, that MMPs are implicated in the functional regulation of a host of non-ECM molecules that include growth factors and their receptors, cytokines and chemokines, adhesion receptors and cell surface proteoglycans, and a variety of enzymes. MMPs therefore play an important role in the control of cellular interactions with and response to their environment in conditions that promote tissue turnover, be they physiological, such as normal development, or pathological, such as inflammation and cancer. This review summarizes some of the recent discoveries that have shed new light on the role of MMPs in physiology and disease. Copyright 2003 John Wiley & Sons, Ltd.
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              Is Open Access

              Interleukin (IL)-23 mediates Toxoplasma gondii–induced immunopathology in the gut via matrixmetalloproteinase-2 and IL-22 but independent of IL-17

              Peroral infection with Toxoplasma gondii leads to the development of small intestinal inflammation dependent on Th1 cytokines. The role of Th17 cells in ileitis is unknown. We report interleukin (IL)-23–mediated gelatinase A (matrixmetalloproteinase [MMP]-2) up-regulation in the ileum of infected mice. MMP-2 deficiency as well as therapeutic or prophylactic selective gelatinase blockage protected mice from the development of T. gondii–induced immunopathology. Moreover, IL-23–dependent up-regulation of IL-22 was essential for the development of ileitis, whereas IL-17 was down-regulated and dispensable. CD4+ T cells were the main source of IL-22 in the small intestinal lamina propria. Thus, IL-23 regulates small intestinal inflammation via IL-22 but independent of IL-17. Gelatinases may be useful targets for treatment of intestinal inflammation.
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                Author and article information

                Journal
                1886
                122234
                European Journal of Microbiology and Immunology
                EuJMI
                Akadémiai Kiadó, co-published with Springer Science+Business Media B.V., Formerly Kluwer Academic Publishers B.V.
                2062-509X
                2062-8633
                1 September 2012
                : 2
                : 3
                : 186-191
                Affiliations
                [ 1 ] Department of Gastroenterology, Infectiology and Rheumatology, Charité — University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany
                [ 2 ] Department of Biochemistry, University of Cambridge, Cambridge, UK
                [ 3 ] Department of Microbiology and Hygiene, Charité — University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany
                [ 4 ] Department of Gastroenterology, Infectiology and Rheumatology, Charité — University Medicine Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, D-12203, Berlin, Germany
                Author notes
                [* ] +49-30-8445-2339, +49-30-8445-4017, christian.freise@ 123456charite.de
                Article
                3
                10.1556/EuJMI.2.2012.3.3
                3962753
                24688764
                Categories
                Original Articles

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