Summary of expression of SPARC protein in cutaneous vascular neoplasms and mimickers
Shakuntala H. MauzoDenái R. MiltonVíctor G. PrietoCarlos A. Torres‐CabalaWei‐Lien WangNitin ChakravartiPriyadharsini NagarajanMichael T. TetzlaffJonathan L. CurryDoina IvanRobert BrownPhyu P. Aung
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Matricellular protein
Osteonectin
SPARC (osteonectin, BM-40) is a matricellular glycoprotein that is expressed in many embryogenic and adult tissues undergoing remodeling or repair. SPARC modulates cellular interaction with the extracellular matrix (ECM), inhibits cell adhesion and proliferation, and regulates growth factor activity. To explore further the function and activity of this protein in tissue homeostasis, we have developed several monoclonal antibodies (MAbs) that recognize distinct epitopes on SPARC. The MAbs bind to SPARC with high affinity and identify SPARC by ELISA, Western blotting, immunoprecipitation, immunocytochemistry, and/or immunohistochemistry. The MAbs were also characterized in functional assays for potential alteration of SPARC activity. SPARC binds to collagen I and laminin-1 through an epitope defined by MAb 293; this epitope is not involved in the binding of SPARC to collagen III. The other MAbs did not interfere with the binding of SPARC to collagen I or III or laminin-1. Inhibition of the anti-adhesive effect of SPARC on endothelial cells by MAb 236 was also observed. Functional analysis of SPARC in the presence of these novel MAbs now confirms that the activities ascribed to this matricellular protein can be assigned to discrete subdomains.
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Osteonectin
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SPARC is a matricellular protein that regulates cell adhesion, extracelluolar matrix production, growth factor activity and cell cycle. This unit describes the purification of SPARC, also termed osteonectin and BM/40, from cultured mammalian cells. Additional information is presented on the purification of recombinant SPARC (rSPARC) from E. coli and from Sf9 cells, as well as its isolation from blood platelets. Assays for the activity of SPARC, de-adhesion and inhibition of cellular proliferation in vitro, are described. The expression of SPARC during remodeling and repair tissue in response to injury identifies it as a therapeutic target for the treatment of fibrotic disease, certain cancers and other disorders in which regulation of angiogenesis is a key factor.
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Secreted protein acidic and rich in cysteine (SPARC), also known as osteonectin or BM-40, is the prototypical matricellular protein. Matricellular proteins are nonstructural secreted proteins that provide an integration between cells and their surrounding extracellular matrix (ECM). Regulation of the ECM is important in maintaining the physiologic function of tissues. Elevated levels of SPARC have been identified in a variety of diseases involving pathologic tissue remodeling, such as hepatic fibrosis, systemic sclerosis, and certain carcinomas. Within the eye, SPARC has been identified in the trabecular meshwork, lens, and retina. Studies have begun to show the role of SPARC in these tissues and its possible role, specifically in primary open-angle glaucoma, cataracts, and proliferative vitreoretinopathy. SPARC may, therefore, be a therapeutic target in the treatment of certain ocular diseases. Further investigation into the mechanism of action of SPARC will be necessary in the development of SPARC-targeted therapy.
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Viral myocarditis is inflammation of the heart muscle as a consequence of infection by common viruses and outcomes for patients range from complete recovery to fatal dilated cardiomyopathy. We investigated the role of the matricellular protein Osteonectin (SPARC) in mitigating the cardiac injury during viral myocarditis. SPARC mRNA and protein expression was induced in the mouse model of viral myocarditis at 7 and 11 days respectively. Under these conditions, SPARC co‐localized with CD‐3‐lymphocytes and VCAM‐endothelial cells. SPARC‐null mice and their wild type (WT) littermates were subjected to human coxsackie‐virusB3 (CVB3)‐induced myocarditis and the absence of SPARC significantly increased cardiac inflammation and mortality as compared to WT mice. We found that SPARC null mice had increased levels of Ly6G+ and Ly6C+ myeloid cells and fewer CD4+ lymphocytes in the heart during viral infection. Importantly, adenoviral overexpression of SPARC in WT animals resulted in improved cardiac function after viral injury as compared to control vector (fractional shortening was 28,2%±0,6 vs 21,2%±0,8 respectively). Collectively these data indicate a role for SPARC in endothelial cell function, leukocyte function and cardiomyocyte contractility. This multifunctional glycoprotein represents an exciting novel target in the treatment of inflammatory heart disease.
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Abstract The impairment of angiogenesis in aging has been attributed, in part, to alterations in proteins associated with the extracellular matrix (ECM). SPARC (secreted protein acidic and rich in cysteine/osteonectin/BM‐40) is a matricellular protein that regulates endothelial cell function as well as cell–ECM interactions. We have previously shown that angiogenesis, as reflected by fibrovascular invasion into subcutaneously implanted polyvinyl alcohol (PVA) sponges, is increased in SPARC‐null mice (6–9 months of age) relative to their wild‐type (WT) counterparts. In this study, we define the influence of aging on (a) the expression of SPARC and (b) fibrovascular invasion into sponge implants in SPARC‐null and WT mice. The expression of SPARC in fibroblasts and endothelial cells derived from young donors (humans mean age less than 30 years and mice 4–6 months of age) and old donors (humans mean age over 65 years and mice 22–27 months of age) decreased 1.6 to 2.3‐fold with age. Analysis of fibrovascular invasion into sponges implanted into old (22–27 months) SPARC‐null and WT mice showed no differences in percent area of invasion or collagenous ECM. Moreover, sponges from old SPARC‐null and WT mice contained similar levels of VEGF that were significantly lower than those from young (4–6 months) mice. In contrast to fibroblasts from young SPARC‐null mice, dermal fibroblasts from old SPARC‐null mice did not migrate farther, proliferate faster, or produce greater amounts of VEGF relative to their old WT counterparts. However, when stimulated with TGF‐β1, primary cells isolated from the sponge implants, and dermal fibroblasts from both old SPARC‐null and WT mice, showed marked increases in VEGF secretion. These data indicate that aging results in a loss of enhanced angiogenesis in SPARC‐null mice, as a result of the detrimental impact of age on cellular functions, collagen deposition, and VEGF synthesis. However, the influence of aging on these processes may be reversed, in part, by growth factor stimulation. © 2005 Wiley‐Liss, Inc.
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Purpose. To investigate the hypothesis that the Matricellular proteins thrombospondin 1 (TSP1), tenascin (TN) and Secreted Protein Acidic and Rich in Cysteine (SPARC) modulate the migration of RPE cells in the epiretinal membranes of proliferative vitreoretinopathy. Methods. Ten PVR epiretinal membranes were studied by immunohistochemical methods in which aggregates of RPE cells were identified by their expression of a broad range of cytokeratins. RPE subsets containing migratory RPE cells were detected by immunoreactivity for the monoclonal antibody RGE53 (which detects an epitope on cytokeratin-18 on motile RPE cells). Co-localisation of the RPE subsets with the glycoproteins TSP-1, SPARC and TN was evaluated. Results. Nineteen migratory RPE (RGE53 positive) subsets and 13 RPE (RGE53 negative) subsets were identified. All of the RGE53+ subsets colocalised with TSP1 and SPARC and 17 with TN. Ten of the RGE53- aggregates stained for TN, 6 for SPARC and 5 for TSP1. The association between the presence of RGE53+ cells in the RPE cell aggregates and TSP1 immunoreactivity in the aggregates was significant (p<0.001), and there was a comparable significant association between RGE53+ cells and SPARC (p<0.001). No such association was detected for RGE53+ cells and TN (p> 0.2). Conclusions. The findings support the concept that the migration of retinal pigment cells in epiretinal membranes is modulated by TSP1 and SPARC and thus that these two proteins ultimately may represent therapeutic targets in the management of the membranes.
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Proliferative Vitreoretinopathy
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Thrombospondin 1
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Commentary to: Osteopontin but not osteonectin favors the metastatic growth of pancreatic cancer cell linesMaria Zhivkova-Galunska, Hassan Adwan, Ergül Eyol, Jörg Kleeff, Armin Kolb, Frank Bergmann and Martin R. Berger
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Pancreatic carcinoma
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