関節リウマチのサイトカインおよび血管増殖因子抑制効果に関する基礎的研究-サイトカインおよびVEGFアンチセンス療法による新しい治療戦略-

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Angiogenesis and synovial cell poliferation are thought to be essential processes in chronic and developmental arthritis, as well as rheumatoid arthritis (RA). Steroids and disease modifying antirheumatic drugs are most widely used as modifying the clinical course of RA. In particular, We examined whether bucillamine (BUC), gold sodium thiomalate (GST), methotrexate (MTX), salazosulfapyridine (SASP) an dexamethazone (DEX) inhibit the production of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (b-FGF). Our results indicated that BUC and DEX could alone inhibit the production of VEGF and mRNA, respectively. Next, we investigated the effect of combinations of these DMARDs including BUC, GST, MTX, SASP and DEX on the production of b-FGF and VEGF. None of the DMARDs or DEX could inhibit b-FGF production when give alone, but a combination of SASP and GST inhibited the prodiction of b-FGF in cultured synoviocytes. On the other hand, all of these combinations cou … More ld inhibit VEGF production except the combinationof MTX and SASP. In the peripheral bloos from obtained 129 RA patients, the serum VEGF levels were correlated with CRP (C-reactive protein) and were found to be significantly decreased 6 months after the commencement of medication compared to their levels before. These results in vitro were supported by the observations in the peripheral blood of patients with RA, that is, in vivo.We mesured the VEGF and b-FGF, and endostatin in peripheral blood and joint fluid obtained from patients with RA and non RA patients using ELISA. The b-FGF and VEGF levels in the peripheral blood and joint fluid of patients with RA were significantly higher than those in the samples from patients without RA, but the endostatin levels were similar and not significantly different between patients with RA and without RA. These results suggested angiogenesis in RA occurs as a result of an imbalance in production between angiogenic growth factors and angiogenesis inhibitors. We will investigate angiogenesis or the inhibitory effects the synovial cell proliferation transplanted in SCID mouse by VEGF antisense or the other angiogenesis inhibitors, like TNP 470. Less