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Induction of the p16INK4a senescence gene as a new therapeutic strategy for the treatment of rheumatoid arthritis

Nature Medicine volume 5, pages 760–767 (1999)Cite this article

Abstract

Synovial tissue affected by rheumatoid arthritis is characterized by proliferation, which leads to irreversible cartilage and bone destruction. Current and experimental treatments have been aimed mainly at correcting the underlying immune abnormalities, but these treatments often prove ineffective in preventing the invasive destruction. We studied the expression of cyclin-dependent kinase inhibitors in rheumatoid synovial cells as a means of suppressing synovial cell proliferation. Synovial cells derived from hypertrophic synovial tissue readily expressed p16INK4a when they were growth-inhibited. This was not seen in other fibroblasts, including those derived from normal and osteoarthritis-affected synovial tissues. In vivo adenoviral gene therapy with the p16INK4a gene efficiently inhibited the pathology in an animal model of rheumatoid arthritis. Thus, the induction of p16INK4a may provide a new approach to the effective treatment of rheumatoid arthritis.

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Figure 1: CDKI expression in fresh synovial tissues and in rheumatoid synovial fibroblasts and other human fibroblasts in conditions of growth inhibition.
Figure 2: Proliferation of growth-inhibited or re-stimulated fibroblasts.
Figure 3: CDKI expression during re-stimulation of cell growth.
Figure 4: Growth inhibition of the rheumatoid synovial fibroblasts by p16INK4a gene transfer.
Figure 5: Expression of the transferred gene and macroscopic effects on AA.
Figure 6: Effects of p16INK4a gene therapy on histopathology of AA.
Figure 7: Histopathological scores of treated joints.

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Acknowledgements

We thank H. Nakamura, K. Uchida and J. Hasegawa for providing synovial samples, Y. Miyazaki for providing the human skin fibroblasts, K.-I. Ohashi for pathological examination of the samples, and S. Endo for his assistance in the animal facility. We are grateful to T. Page for critical review of the manuscript. This study was supported by a grant-in-aid for scientific research (08557037) from the Ministry of Education, Science, Sports, and Culture, Japan.

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Authors and Affiliations

  1. First Department of Internal Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, 113-8519, Tokyo, Japan

    Ken Taniguchi, Hitoshi Kohsaka, Naoki Inoue & Nobuyuki Miyasaka

  2. Second Department of Internal Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, 113-8519, Tokyo, Japan

    Yoshio Terada & Hiroshi Ito

  3. Department of Pathology and Immunology, School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, 113-8519, Tokyo, Japan

    Katsuiku Hirokawa

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  1. Ken Taniguchi
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Correspondence to Hitoshi Kohsaka.

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Taniguchi, K., Kohsaka, H., Inoue, N. et al. Induction of the p16INK4a senescence gene as a new therapeutic strategy for the treatment of rheumatoid arthritis. Nat Med 5, 760–767 (1999). https://doi.org/10.1038/10480

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