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Departments of
*
Bioregulatory Medicine and Rheumatology,
Homeostasis Medicine, and
Pathology and Immunology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
In rheumatoid synovial tissues, synovial fibroblasts are activated
by proinflammatory cytokines and proliferate to develop hyperplastic
pannus tissues, which irreversibly damage the affected joints. We
recently reported that the cyclin-dependent kinase inhibitors
p16INK4a and p21Cip1 are not expressed in vivo
in rheumatoid synovial fibroblasts, but are readily inducible in vitro.
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 this study, we show that another animal model of
rheumatoid arthritis, 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 when the treatment was conducted after the arthritis
had developed. Furthermore, the effects included suppression of the
expression of proinflammatory cytokines such as IL-1ß, IL-6, and
TNF-
. Our results demonstrate that the ectopic expression of
cyclin-dependent kinase inhibitors not only prevents synovial
overgrowth but also ameliorates the proinflammatory milieu in the
affected joints. The induction of p21Cip1 in rheumatoid
synovial tissues by pharmacological agents may also be an effective
strategy to treat rheumatoid arthritis.
This article has been cited by other articles:
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 J. C. Scatizzi, J. Hutcheson, E. Bickel, J. M. Woods, K. Klosowska, T. L. Moore, G. K. Haines III, and H. Perlman p21Cip1 Is Required for the Development of Monocytes and Their Response to Serum Transfer-induced Arthritis Am. J. Pathol., May 1, 2006; 168(5): 1531 - 1541. [Abstract] [Full Text] [PDF]
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Y. Nonomura, H. Kohsaka, K. Nagasaka, and N. Miyasaka Gene Transfer of a Cell Cycle Modulator Exerts Anti-Inflammatory Effects in the Treatment of Arthritis J. Immunol., November 1, 2003; 171(9): 4913 - 4919. [Abstract] [Full Text] [PDF]
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H. Perlman, K. Bradley, H. Liu, S. Cole, E. Shamiyeh, R. C. Smith, K. Walsh, S. Fiore, A. E. Koch, G. S. Firestein, et al. IL-6 and Matrix Metalloproteinase-1 Are Regulated by the Cyclin-Dependent Kinase Inhibitor p21 in Synovial Fibroblasts J. Immunol., January 15, 2003; 170(2): 838 - 845. [Abstract] [Full Text] [PDF]
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