Background Angiogenesis, which is the growth of new capillaries from pre-existing blood vessels, is an essential feature of rheumatoid arthritis (RA). Neovascularisation might be triggered by several factors, such as cytokines, growth factors and adhesion molecules.
Objectives Gliostatin/thymidine phosphorylase (GLS/TP) is known to have angiogenic and arthritogenic activities. The expression of GLS in serum from patients with rheumatoid arthritis (RA) was significantly correlated with disease activity. The purpose of this study was to elucidate whether GLS is involved in the regulation of the angiogenic cytokine vascular endothelial growth factor (VEGF) in RA.
Methods Synovial tissue from patients with RA was labelled immunohistochemically with antibodies against GLS and VEGF. Fibroblast-like synoviocytes (FLSs) from patients with RA were cultured and stimulated with recombinant human GLS (rHuGLS) and TNFa. The expression level of VEGF mRNA was measured by real time PCR analysis. VEGF protein levels in conditioned media were measured using an enzyme-linked immunosorbent assay.
Results Immunohistochemistry showed that GLS/TP and VEGF were detectable in the synovial lining cells of patients with RA. In cultured FLSs, both VEGF mRNA and protein levels were markedly increased by TNFa treatment in a dose-dependent manner. rHuGLS increased VEGF mRNA expression in a concentration-dependent manner. The time course of VEGF mRNA expression induced by rHuGLS exhibited a bell-shaped profile. We detected high concentrations of VEGF 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.
Conclusions These findings indicate that GLS and VEGF have synergistic effects on angiogenesis in rheumatoid synovitis, and that GLS has a role in regulating VEGF. We therefore hypothesise that the suppression of GLS activity could be an effective therapy in RA.
Tanikawa T, et al. Gliostatin/thymidine phosphorylase-regulated vascular endothelial growth-factor production in human fibroblast-like synoviocytes. Rheumatol Int. 2007;27:553-559.
Yamagami T, et al. FK506 inhibition of gliostatin/thymidine phosphorylase production induced by tumor necrosis factor-a in rheumatoid fibroblast-like synoviocytes. Rheumatol Int. 2011; 37:903-909.
Disclosure of Interest : Y. Kawaguchi: None declared, Y. Waguri-Nagaya Grant/research support: Biomet Japan,Inc,Chugai Pharmaceutical Co.,Ltd.,Astellas Pharma Inc., Merck Sharp&Dohme Co.,AbbVie Japan Co.,Ltd.,Ono Pharmaceutical Co.,Ltd., N. Tatematsu: None declared, M. Kobayashi: None declared, H. Goto: None declared, M. Nozaki: None declared, K. Ikuta: None declared, M. Aoyama: None declared, K. Asai: None declared, T. Otsuka: None declared