Cell Cycle Control for Treatment of Rheumatoid Arthritis

• Project/Area Number: 10470124
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: 内科学一般
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: MIYASAKA Nobuyuki Professor School of Medicine, Tokyo Medical and Dental University, 医学部, 教授 (30157622)
• Co-Investigator(Kenkyū-buntansha): KOHSAKA Hitoshi School of Medicine, Tokyo Medical and Dental University, 医学部, 助手 (00251554)
• Project Period (FY): 1998 – 1999
• Project Status: Completed (Fiscal Year 1999)
• Budget Amount: ¥12,500,000 (Direct Cost: ¥12,500,000); Fiscal Year 1999: ¥3,000,000 (Direct Cost: ¥3,000,000); Fiscal Year 1998: ¥9,500,000 (Direct Cost: ¥9,500,000)
• Keywords: rheumatoid arthritis / CDKI / gene therapy / 滑膜増殖 / サイクリン / 遺伝子療法

Research Abstract

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.

Research Products

• [Publications] Taniguchi K,Kohsaka H,Miyasaka N et al.: "Induction of p16INK4a Senescence Gene as a New Therapeutic Strategy for the Treatment of Rhematoid Arthritis"Nature Medicine. 5,7. 760-767 (1999)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Kohsaka H,Taniguchi K,Miyasaka N et al.: "Characteristic Inducibility of p16INK4a in Rheumatoid Synovial Fibroblasts"Arthritis Rheum. 46,9. S86 (1999)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Nasu K,kohsaka H,Nonomura Y,Miyasaka N: "Gene Transfer of Senescence Gene p16INK4a Supresses Collagen-induced Arthritis by Inhibiting Cell Cycle and Cytokine Production of the Synovial Cells."Arthritis Rheum. 46,9. S107 (1999)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] 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)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Taniguchi K, Kohsaka H, Inoue N, Terada Y, Ito H, Hirokawa K, and Miyasaka N.: "Induction of p16INK4a Senescence Gene as a New Therapeutic Strategy for the Treatment of Rheumatoid Arthritis."Nature Medicine. 5(7). 760-767 (1999)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] 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)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Nasu K, Kohsaka H, Nonomura Y, Miyasaka N.: "Gene Transfer of Senescence Gene p16INK4a Suppresses Collagen-induced Arthritis by Inhibiting Cell Cycle and Cytokine Production of the Synovial Cells."Arthritis Rheum. 46(9). S107 (1999)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] 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)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Taniguchi K, Kohsaka H, Miyasaka N et al.: "Induction of p16INK4a Senescence Gene as a New Therapeutic Strategy for the Treatment of Rheumatoid Arthritis"Nature Medicine. 5,7. 760-767 (1999)
• [Publications] Kohsaka H, Taniguchi K, Miyasaka N et al.: "Characteristic Inducibility of p16INK4a in Rheumatoid Synovial Fibroblasts"Arthritis Rheum. 46,9. S86 (1999)
• [Publications] Nasu K, Kohsaka H, Nonomura Y, Miyasaka N: "Gene Transfer of Senescence Gene p16INK4a Supresses Collagen-induced Arthritis by Inhibiting Cell Cycle and Cytokine Production of the Synovial Cells."Arthritis Rheum. 46,9. S107 (1999)
• [Publications] 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)