Cell Cycle Control for Treatment of Rheumatoid Arthritis

细胞周期控制治疗类风湿关节炎

• 批准号: 10470124
• 负责人: MIYASAKA Nobuyuki
• 金额: $ 8万
• 依托单位: Tokyo Medical and 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: 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-10470124/
• 关键词: rheumatoid arthritis; CDKI; gene therapy; 滑膜増殖; サイクリン; 遺伝子療法

In rheumatoid synovial tissues, synovial fibroblasts are activated by pro-inflammatory cytokines and proliferate to develop hyperplastic pannus tissues, which irreversibly damage the affected joints. We recently reported that the cyclin-dependent kinase inhibitors (CDKIs) p16INK4a and p21Cip 1 are not expressed in vivo in rheumatoid synovial fibroblasts, but are readily inducible in vitro (1). This observation was followed by the successful treatment of rat adjuvant arthritis by local p16INK4a gene transfer, showing that the inhibition of the cell cycle of the synovial cells ameliorates the arthritis. In the present study, we show that another animal model of rheumatoid arthritis (RA), murine collagen-induced arthritis, can be effectively treated by local gene transfer of p21Cip1 as well as that of p16INK4a. The anti-arthritic effects were observed even in the treatment after the arthritis had developed. Furthermore, the effects included suppression of the expression of pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α. Our data demonstrate that the ectopic expression of CDKIs not only prevents synovial overgrowth but also ameliorates the pro-inflammatory milieu in the affected joints and suggest that the induction of p21Cip1 in rheumatoid synovial tissues may also be an effective strategy to treat RA.

在类风湿滑膜组织中，滑膜成纤维细胞被促炎细胞因子激活并增殖，形成增生性血管膜组织，对受影响的关节造成不可逆转的损害。我们最近报道，细胞周期蛋白依赖性激酶抑制因子(CDKI)p16INK4a和p21Cip 1在类风湿滑膜成纤维细胞中不表达，但在体外很容易被诱导[1]。随后通过局部p16INK4a基因转移成功地治疗了大鼠佐剂性关节炎，表明抑制滑膜细胞的细胞周期可以改善关节炎。在本研究中，我们证明了另一种类风湿性关节炎(RA)的动物模型，即小鼠胶原性关节炎，可以通过p21Cip1和p16INK4a的局部基因转移有效地治疗。即使在关节炎形成后的治疗中也观察到了抗关节炎的作用。此外，其作用还包括抑制促炎细胞因子的表达，如IL-1β、IL-6和肿瘤坏死因子-α。我们的研究结果表明，CDKI的异位表达不仅可以防止滑膜过度生长，还可以改善关节中的促炎环境，提示在类风湿滑膜组织中诱导p21Cip1的表达也可能是治疗RA的有效策略。

项目成果

Kohsaka H,Taniguchi K,Miyasaka N et al.: "Characteristic Inducibility of p16INK4a in Rheumatoid Synovial Fibroblasts"Arthritis Rheum. 46,9. S86 (1999)

Kohsaka H、Taniguchi K、Miyasaka N 等人：“类风湿滑膜成纤维细胞中 p16INK4a 的特征诱导性”关节炎大黄。

Kohsaka H, Taniguchi K, Nagasaka K, Nonomura Y, Nasu K, Miyasaka N.: "Characteristic Inducibility of p16INK4a in Rheumatoid Synovial Fibroblasts."Arthritis Rheum. 46(9). S86 (1999)

Kohsaka H、Taniguchi K、Nagasaka K、Nonomura Y、Nasu K、Miyasaka N.：“类风湿滑膜成纤维细胞中 p16INK4a 的特征诱导性。”关节炎大黄。

Nonomura Y, Kohsaka H, Nasu K, Taniguchi K, Miyasaka N.: "Supression of Arthritis by Forcrd Expression of Cyclin-dependent Kinase Inhibitor p21Cip1 Gene into the Joints"Arthritis Rheum. 46,9. S107 (1999)

Nonomura Y、Kohsaka H、Nasu K、Taniguchi K、Miyasaka N.：“通过将细胞周期蛋白依赖性激酶抑制剂 p21Cip1 基因强制表达到关节来抑制关节炎”关节炎大黄。

Nonomura Y,Kohsaka H,Nasu K,Taniguchi K,Miyasaka N.: "Supression of Arthritis by Forcrd Expression of Cyclin-dependent Kinase Inhibitor p21Cip1 Gene into the Joints"Arthritis Rheum. 46,9. S107 (1999)

Nonomura Y、Kohsaka H、Nasu K、Taniguchi K、Miyasaka N.：“通过将细胞周期蛋白依赖性激酶抑制剂 p21Cip1 基因强制表达到关节来抑制关节炎”关节炎大黄。

Nonomura Y, Kohsaka H, Nasu K, Taniguchi K, Miyasaka N.: "Suppression of Arthritis by Forced Expression of Cyclin-dependent Kinase Inhibitor p21Cip1 Gene into the Joints."Arthritis Rheum. 46(9). S107 (1999)

Nonomura Y、Kohsaka H、Nasu K、Taniguchi K、Miyasaka N.：“通过将细胞周期蛋白依赖性激酶抑制剂 p21Cip1 基因强制表达到关节来抑制关节炎。”关节炎大黄。