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

已知Gliostatin/thymidine phosphorylase（GLS/TP）具有血管生成和关节炎生成活性。我们以前证明，第一次，显着更高的浓度GLS/TP类风湿关节炎（RA）患者的血清和滑液相比，骨关节炎或正常对照组。在体外培养的RA成纤维样滑膜细胞（FLS）中，IL-1、TNF α等炎性细胞因子可上调GLS的表达，本研究旨在探讨GLS/TP是否参与RA血管生成因子血管内皮生长因子（VEGF）的调节。用重组人GLS（rHuGLS）和白细胞介素（IL）-1 β刺激RA患者滑膜成纤维样细胞（FLS），免疫组化显示RA患者滑膜衬里层细胞表达GLS/TP和VEGF。GLS/TP和VEGF在骨关节炎患者的滑膜标本中的检测比RA患者的更弱。在培养的FLS中，VEGF mRNA和蛋白水平均被rHuIL-1β处理显著增加。rHuGLS以剂量依赖性方式增加VEGF mRNA表达。我们在用rHuGLS（300 ng/ml）处理的FLS的培养上清液中检测到高浓度的VEGF 165蛋白，其与在RA患者的滑液中发现的GLS水平相当。这些发现表明GLS/TP和VEGF在类风湿性滑膜炎中对血管生成具有协同作用，并且GLS/TP具有调节VEGF的作用

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