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* Clinical Immunology, RIKEN Research Center of Allergy and Immunology, Yokohama, Japan;
Department of Medicine and Rheumatology, Graduate School, Tokyo Medical and Dental University, and 21st Century Center of Excellence Program for the Frontier Research on Molecular Destruction and Reconstruction of Tooth and Bone, Tokyo, Japan;
Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan; and
Banyu Tsukuba Research Institute, Banyu Pharmaceutical, Tsukuba, Japan
Intraarticular gene transfer of cyclin-dependent kinase (CDK) inhibitors to suppress synovial cell cycling has shown efficacy in treating animal models of rheumatoid arthritis. Endogenous CDK inhibitors also modulate immune function via a CDK-independent pathway. Accordingly, systemic administration of small molecules that inhibit CDK may or may not ameliorate arthritis. To address this issue, alvocidib (flavopiridol), known to be tolerated clinically for treating cancers, and a newly synthesized CDK4/6-selective inhibitor were tested for antiarthritic effects. In vitro, they inhibited proliferation of human and mouse synovial fibroblasts without inducing apoptosis. In vivo, treatment of collagen-induced arthritis mice with alvocidib suppressed synovial hyperplasia and joint destruction, whereas serum concentrations of anti-collagen type II (CII) Abs and proliferative responses to CII were maintained. Treatment was effective even when therapeutically administered. Treated mice developed arthritis after termination of treatment. Thus, immune responses to CII were unimpaired. The same treatment ameliorated arthritis induced by K/BxN serum transfer to lymphocyte-deficient mice. Similarly, the CDK4/6-selective inhibitor suppressed collagen-induced arthritis. Both small-molecule CDK inhibitors were effective in treating animal models of rheumatoid arthritis not by suppressing lymphocyte function. Thus, the two small-molecule CDK inhibitors ameliorated arthritis models in a distinctive way, compared with other immunosuppressive drugs.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work is supported by grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology, Japan.
2 Address correspondence and reprint requests to Dr. Hitoshi Kohsaka, Department of Medicine and Rheumatology, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. E-mail address: kohsaka.rheu{at}tmd.ac.jp
3 Abbreviations used in this paper: RA, rheumatoid arthritis; CDK, cyclin-dependent kinase; CDKI, CDK inhibitor; smCDK, small-molecule CDK; CIA, collagen-induced arthritis; CII, type II collagen; FLS, fibroblast-like synoviocyte; MFLS, mouse fibroblast-like synoviocyte; RB, retinoblastoma; LN, lymph node.
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