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      Osteopontin Function in Pathology: Lessons from Osteopontin-Deficient Mice


      Cardiorenal Medicine

      S. Karger AG

      Injury, Knockout mice, Osteopontin, Macrophages

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          Osteopontin (OPN) is a soluble secreted phosphoprotein that binds with high affinity to several different integrins. While numerous activities have been ascribed to OPN in vitro, and several in vivo functions have been suggested for the molecule, including much attention focused recently on OPN in different pathologies, the actual role that the protein plays in mammalian physiology remains conjectural. Analysis of recently developed strains of mice lacking OPN because of a targeted disruption of its gene promises to provide important information on this issue. Here, we review the data implicating OPN as functioning in a variety of pathologic conditions as well as the initial results generated with the OPN knockout mice, with particular focus on the question of whether OPN has a protective or a damaging effect in different pathologies. These data will be important to the definition of how OPN contributes to mammalian physiology and pathophysiology.

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          Most cited references 10

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          NF-κB Mediates αvβ3 Integrin-induced Endothelial Cell Survival

          The αvβ3 integrin plays a fundamental role during the angiogenesis process by inhibiting endothelial cell apoptosis. However, the mechanism of inhibition is unknown. In this report, we show that integrin-mediated cell survival involves regulation of nuclear factor-kappa B (NF-κB) activity. Different extracellular matrix molecules were able to protect rat aorta- derived endothelial cells from apoptosis induced by serum withdrawal. Osteopontin and β3 integrin ligation rapidly increased NF-κB activity as measured by gel shift and reporter activity. The p65 and p50 subunits were present in the shifted complex. In contrast, collagen type I (a β1-integrin ligand) did not induce NF-κB activity. The αvβ3 integrin was most important for osteopontin-mediated NF-κB induction and survival, since adding a neutralizing anti-β3 integrin antibody blocked NF-κB activity and induced endothelial cell death when cells were plated on osteopontin. NF-κB was required for osteopontin- and vitronectin-induced survival since inhibition of NF-κB activity with nonphosphorylatable IκB completely blocked the protective effect of osteopontin and vitronectin. In contrast, NF-κB was not required for fibronectin, laminin, and collagen type I–induced survival. Activation of NF-κB by osteopontin depended on the small GTP-binding protein Ras and the tyrosine kinase Src, since NF-κB reporter activity was inhibited by Ras and Src dominant-negative mutants. In contrast, inhibition of MEK and PI3-kinase did not affect osteopontin-induced NF-κB activation. These studies identify NF-κB as an important signaling molecule in αvβ3 integrin-mediated endothelial cell survival.
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            Definition of a specific interaction between the early T lymphocyte activation 1 (Eta-1) protein and murine macrophages in vitro and its effect upon macrophages in vivo

             P Singh,  R Patarca,  RP Singh (1990)
            The Eta-1 gene specifies a secreted product of activated T cells and is associated with genetic resistance to infection by an obligate intracellular bacterium. Previous studies have suggested that eta-1 might affect the ability of macrophages to migrate to the site of bacterial infection and/or to inhibit intracellular bacterial growth. We therefore examined the interaction of eta-1 with macrophages in vitro and in vivo. We find that macrophages express approximately 10(4) eta-1 receptors/cell and each receptor has a Kd of approximately 5 x 10(-10) M. The subsequence of eta-1 containing an RGD motif is required for binding because a synthetic peptide containing the eta-1 RGD domain inhibited protein attachment to macrophages. We also found that subcutaneous inoculation of mice with eta-1 resulted in a cellular infiltrate comprised primarily of macrophages. We propose that the interaction between eta-1 and its receptor on macrophages results in a change in macrophage physiology resulting in accumulation of these cells at extravascular sites.
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              A Biochemical Characterization of the Binding of Osteopontin to Integrins αvβ1and αvβ5


                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                April 1999
                23 April 1999
                : 7
                : 2
                : 103-113
                Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, N.J., USA
                20591 Exp Nephrol 1999;7:103–113
                © 1999 S. Karger AG, Basel

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                Page count
                Figures: 2, Tables: 1, References: 91, Pages: 11
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                Cardiovascular Medicine, Nephrology

                Osteopontin, Macrophages, Injury, Knockout mice


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