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-

细胞因子和血管生长因子对类风湿性关节炎抑制作用的基础研究 - 利用细胞因子和VEGF反义疗法的新治疗策略 -

• 批准号: 10670433
• 负责人: NAGASHIMA Masakazu
• 金额: $ 1.92万
• 依托单位: NIPPON MEDICAL SCHOOL
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670433/
• 关键词: Rheumatoid Arthritis; Angiogenesis; Vascular endothelial growth factor (VEGF); Basic fibroblast growth factor (b-FGF); Endostatin; Cultured synoviocytes; Disease modifying antirheumatic drugs (DMARDs); 疾患修飾性抗リウマチ剤; IL-6

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

血管生成和滑膜细胞增殖被认为是慢性和发育性关节炎以及类风湿性关节炎（RA）的基本过程。类固醇和疾病缓解抗风湿药物是最广泛使用的修改类风湿关节炎的临床过程。特别地，我们检测了布西拉明（布克）、硫代苹果酸金钠（GST）、甲氨蝶呤（MTX）、柳氮磺胺吡啶（SASP）和地塞米松（DEX）是否抑制血管内皮生长因子（VEGF）和碱性成纤维细胞生长因子（b-FGF）的产生。结果表明，布克和地塞米松单独作用可抑制VEGF和mRNA的表达。接下来，我们研究了这些DMARD（包括布克、GST、MTX、SASP和DEX）的组合对b-FGF和VEGF产生的影响。DMARDs和DEX单独给药均不能抑制b-FGF的产生，但SASP和GST联合给药可抑制b-FGF的产生。另一方面，所有这些组合都可以 ...更多信息 除MTX和SASP联合应用外，其余4种药物均能抑制VEGF的生成。在获得的129例RA患者的外周血中，血清VEGF水平与CRP（C-反应蛋白）相关，并且发现在开始用药后6个月与其之前的水平相比显著降低。本研究采用ELISA法检测了RA患者和非RA患者外周血和关节液中VEGF、b-FGF和Endostatin的含量。RA患者外周血和关节液中b-FGF和VEGF水平显著高于非RA患者，而内皮抑素水平相似，但无显著性差异。这些结果表明，RA中的血管生成是由于血管生成生长因子和血管生成抑制剂之间的生产不平衡而发生的。我们将研究VEGF反义核酸或其他血管生成抑制剂（如TNP 470）对SCID小鼠移植滑膜细胞增殖的抑制作用。少

项目成果

Gunji N, Nagashima M, Yoshino S: "Expression of κ-opioid receptor mRNA in human peripheral blood lymphocytes and the relationship between its expression and the inflammatory chnges in rheumatoid arthritis."Rheumatol Int. 20 (in press). (2000)

Gunji N、Nagashima M、Yoshino S：“人外周血淋巴细胞中 κ-阿片受体 mRNA 的表达及其表达与类风湿性关节炎炎症变化的关系。”Rheumatol Int 20（出版中）。

M.Nagashima et al.: "Inhibitory effects of antirheumatic drugs on vascular endothelial growth factor in cultured rheumatoid synovial cells" Clinical and Experimental Immunology. accepted. (1999)

M.Nagashima 等人：“抗风湿药物对培养的类风湿滑膜细胞中血管内皮生长因子的抑制作用”临床和实验免疫学。

永島正一他(分担): "別冊整形外科No.34,慢性関節リウマチ-最近の動向" 南江堂, 223 (1998)

Shoichi Nagashima 等人（撰稿人）：《Bessatsu Orthopedics No. 34，慢性类风湿性关节炎 - 最近趋势》Nankodo，223 (1998)

Nagashima M: "The imbalance between vascular endothelial growth factor and endostatin in patients with rheumatoid arthritis."J Rheumatol. 27 (in press). -Nagashima M. et al (2000)

Nagashima M：“类风湿性关节炎患者血管内皮生长因子和内皮抑素之间的不平衡。”J Rheumatol。

Nagashima M, et al: "IgG rheumatoid factor in early rheumatoid arthritis as a predictor of radiological changes and disease activity"Japanese J Rheumatol. 9. 159-166 (1999)

Nagashima M，等人：“早期类风湿性关节炎中的 IgG 类风湿因子作为放射学变化和疾病活动的预测因子”日本 J Rheumatol。