International Immunology, Vol. 13, No. 6, 723-731,
June 2001
© 2001 Japanese Society for Immunology
Suppression of arthritis by forced expression of cyclin-dependent kinase inhibitor p21Cip1 gene into the joints
Departments of Bioregulatory Medicine and Rheumatology,
1 Homeostasis Medicine and Nephrology, and
2 Craniofacial Molecular Embryology, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan
Correspondence to: H. Kohsaka
Rheumatoid synovial fibroblasts (RSF) express cyclin-dependent kinase (CDK) inhibitors p16INK4a and p21Cip1 when they are growth-inhibited in vitro. The induction of p16INK4a is characteristic of RSF and intra-articular p16INK4a gene therapy has been shown to suppress adjuvant arthritis (AA) of rats. The other inducible CDK inhibitor, p21Cip1, has multiple functions depending on the cell type. They include inhibition of CDK as well as promotion of active CDK complex formation and induction of apoptosis. This study is to discern the biological effects of p21Cip1 gene transfer into RSF and its therapeutic effects on AA. A recombinant adenovirus containing a human p21Cip1 gene and control adenoviruses were prepared. RSF infected with these viruses were examined for their cell growth. Apoptotic cell death was evaluated by nuclear staining and DNA fragmentation analysis. In vivogene therapy of rat AA was carried out by intra-articular injection of the viruses. Severity of the arthritis was clinically scored. The treated joints were examined histologically and proliferating cell nuclear antigens (PCNA) were detected immunohistochemically. The adenoviral p21Cip1 gene transfer inhibited growth of RSF without inducing apoptosis. p21Cip1 gene therapy suppressed AA clinically and histologically. The effects were comparable to p16INK4a gene therapy. PCNA expression was reduced in the p21Cip1-treated joints. The adenoviral gene transfer of p21Cip1 ameliorated rat AA. The effect was attributable to inhibition of proliferation. Because p21Cip1 is induced more easily by many chemicals than p16INK4a, it also appears to be a feasible target in developing anti-rheumatic drugs.
Keywords: adjuvant arthritis, apoptosis, cyclin-dependent kinase inhibitor, p21Cip1, rheumatoid arthritis
Transmitting editor: T Sasazuki
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