Angiogenic action of gliostatin/thymidine phosphorylase and vascular endothelial growth factor in rheumatoid arthritis and its molecular mechanism

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Gliostatin/thymidine phosphorylase (GLS/TP) is known to have angiogenic and arthritogenic activities. We previously demonstrated, for the first time, significantly higher concentrations of GLS/TP in the sera and synovial fluids of patients with rheumatoid arthritis (RA) compared to those with osteoarthritis or normal controls. In cultured RA fibroblast-like synoviocytes (FLSs), GLS expression was found to be up-regulated by inflammatory cytokines, such as IL-i and tumour-necrosis factor (TNF)α.The purpose of this study was to elucidate whether GLS/TP is involved in the regulation of the angiogenic cytokine vascular endothelial growth factor (VEGF) in RA. Fibroblast-like synoviocytes (FLSs) from patients with RA were cultured and stimulated with recombinant human GLS (rHuGLS) and interleukin (IL)-1β.Immunohistochemistry showed that GLS/TP and VEGF were detectable in the synovial lining cells from RA patients. GLS/TP and VEGF were even more weakly detected in synovial specimens from osteoarthritis patients than these from RA patients. In cultured FLSs, both VEGF mRNA and protein levels were markedly increased by rHuIL-1β treatment. rHuGLS increased VEGF mRNA expression in a dose-dependent manner. We detected high concentrations of VEGF165 protein in culture supernatants from FLSs treated with rHuGLS (300 ng/ml), which were comparable to GLS levels found in synovial fluid of RA patients. These findings indicate that GLS/TP and VEGF have synergistic effects on angiogenesis in rheumatoid synovitis, and that GLS/TP has a role in regulating VEGF