New Therapy for Rheumatoid Arthritis with Cell Cycle Regulators

细胞周期调节剂治疗类风湿关节炎的新疗法

• 批准号: 12557048
• 负责人: KOHSAKA Hitoshi
• 金额: $ 8.51万
• 依托单位: Tokyo Medical & Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12557048/
• 关键词: rheumatoid arthritis; cell cycle; gene therapy; 慢性関節リウマチ

Forced expression of a cyclin-dependent kinase inhibitor (CDKI) gene, pl6INKa and p21Cipl in the synovial tissues was effective in treating animal models of rheumatoid arthritis (RA). Synovial hyperplasia in the treated joints was suppressed, reflecting the inhibitory effect of p16INKa and p21Cipl on cell cycle progression. Additionally, lymphocyte infiltration, expression of inflammatory cytokines, and destruction of the bone and cartilage were inhibited. To discern how the cell cycle regulator gene exerted such complementary effects, we investigated gene expression by rheumatoid synovial fibroblasts with or without the p21 gene transferred. DNA array and subsequent conventional analyzes have demonstrated downregulation of various inflammatory mediators and tissue-degrading proteinases that are critically involved in the pathology of RA. These molecules included IL-6, -8, type I IL-1 receptor (IL-1R1), monocyte chemoattractant protein-1, macrophage inflammatory protein-3α, cathepsins B and K, MMP-1 and -3. Downregulation of IL-1R1 by p21Cipl actually resulted in attenuated responsiveness to IL-1. Inhibition of the inflammatory gene expression by p21 was seen even when IL-1 is absent. This IL-1R1-independent suppression accompanied inactivation of NF-kB and activator protein-1 transcription factors. These multiple effects could assist inhibition of cell cycling in ameliorating the arthritis, and suggest a heretofore unexplored relationship between CDKIs and immunological effector molecules.

在滑膜组织中强制表达细胞周期蛋白依赖性激酶抑制剂（CDKI）基因pl6INKa和p21Cipl对类风湿关节炎（RA）动物模型有效。治疗后关节滑膜增生受到抑制，反映了p16INKa和p21Cipl对细胞周期进展的抑制作用。此外，淋巴细胞浸润、炎症细胞因子的表达以及骨和软骨的破坏均受到抑制。为了了解细胞周期调节基因如何发挥这种互补作用，我们研究了p21基因转移或不转移p21基因的类风湿性滑膜成纤维细胞的基因表达。DNA阵列和随后的常规分析表明，各种炎症介质和组织降解蛋白酶的下调与RA的病理密切相关。这些分子包括IL-6、-8、I型IL-1受体（IL-1R1）、单核细胞趋化蛋白-1、巨噬细胞炎症蛋白-3α、组织蛋白酶B和K、MMP-1和-3。p21Cipl下调IL-1R1实际上导致对IL-1的反应性减弱。即使IL-1缺失，p21也能抑制炎症基因的表达。这种与il - 1r1无关的抑制伴随着NF-kB和激活蛋白-1转录因子的失活。这些多重作用可能有助于抑制细胞循环以改善关节炎，并提示CDKIs与免疫效应分子之间迄今未被探索的关系。

项目成果

Kohsaka, H, Nasu, K, Nonornura, Y, Miyasaka, N.: "Treatment of Arthritis with Cyclin-dependent Kinase Inhibitor Gene"Jpn J Clin Immunol. 23(6). 550-552 (2000)

Kohsaka，H，Nasu，K，Nonornura，Y，Miyasaka，N.：“用细胞周期蛋白依赖性激酶抑制剂基因治疗关节炎”Jpn J Clin Immunol。

Kohsaka, H: "Gene therapy for arthritis"Modern Rheumatol. 10(2). 78-82 (2000)

Kohsaka，H：“关节炎的基因疗法”现代风湿病。

Nishio, J, Kohsaka, H, Shimamura, T, Hamuro, J, Miyasaka, N.: "Abundant Expression of Common Cytokine Receptor γ Chain (CD132) in the Rheumatoid Joints"J Rheumatol. 28(2). 240-244 (2000)

Nishio, J、Kohsaka, H、Shimamura, T、Hamuro, J、Miyasaka, N.：“类风湿关节中常见细胞因子受体 γ 链 (CD132) 的丰富表达”J Rheumatol 28(2)。 2000)

Nasu, K, Kohsaka, H, Nonomura, Y, Terada, Y, Ito, H, Hirokawa, K, Miyasaka, N.: "Adenoviral Transfer of Cyclin-Dependent Kinase Inhibitor Genes Suppresses Collagen-Induced Arthritis in Mice"J Immunol. 165(12). 7246-7252 (2000)

Nasu, K, Kohsaka, H, Nonomura, Y, Terada, Y, Ito, H, Hirokawa, K, Miyasaka, N.：“细胞周期蛋白依赖性激酶抑制剂基因的腺病毒转移抑制小鼠胶原诱导的关节炎”J 免疫学杂志。

Kohsaka H,Nasu K,Nonomura Y,Miyasaka N.: "Treatment of Arthritis with Cyclin-dependent Kinase Inhibitor Gene."Jpn J Clin Immunol. 23(6):. 550-552 (2000)

Kohsaka H，Nasu K，Nonomura Y，Miyasaka N.：“用细胞周期蛋白依赖性激酶抑制剂基因治疗关节炎”。Jpn J Clin Immunol。