2005 Fiscal Year Final Research Report Summary
| Project/Area Number |
13043012
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
KOHSAKA Hitoshi Tokyo Medical and Dental University. Tokyo Medical and Dental University Graduate School, Department of Bioregulation, Associate Professor, 大学院医歯学総合研究科, 助教授 (00251554)
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| Co-Investigator(Kenkyū-buntansha) |
TERADA Yoshio Tokyo Medical and Dental University, Tokyo Medical and Dental University Graduate School, Department of Homeostasis Medicine and Nephrology, Associate Professor, 大学院医歯学総合研究科, 助教授 (30251531)
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| Project Period (FY) |
2001 – 2005
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| Keywords | rheumatoid arthritis / enhropathy / animal models / cell cycle |
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| Research Abstract |
Intra-articular gene transfer of cyclin-dependent kinase inhibitors (CDKI) to suppress synovial cell cycling has shown efficacy in treating animal models of rheumatoid arthritis (RA). CDKIs also modulate immune function via a CDKindependent pathway. Accordingly, systemic administration of small molecules that inhibit. CDK might ameliorate arthritis. In order to address this issue, alvocidib (flavopiridol), known to be tolerated clinically for treating cancers, and also a newly synthesized CDK4/6-selective inhibitor were tested for anti-arthritic effects. In vitro, they inhibited proliferation of human and mouse synovial fibroblasts without inducing apoptosis. In vivo, treatment of collagen-induced arthritis (CIA) mice with alvocidib suppressed synovial hyperplasia and joint destruction while serum concentrations of anti-type II collagen (Cll) antibodies and proliferative responses to Cll were maintained. Treatment was effective even when therapeutically administered. Treated mice developed arthritis after termination of treatment. Thus, immune responses to Cll were unimpaired. The same treatment ameliorated arthritis induced by K/BxN serum transfer to lymphocyte-deficient mice. Similarly, the CDK4/6-selective inhibitor suppressed CIA. Both small molecule (sm) CDK inhibitors were effective in treating animal models of RA not by suppressing lymphocyte function. We believe that smCDK inhibitors hold promise as a new class of anti-rheumatic drugs that inhibit a distinct phase of rheumatoid pathogenesis
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