Successful Treatment of Animal Models of Rheumatoid Arthritis with Small-Molecule Cyclin-Dependent Kinase Inhibitors

摘要: Intraarticular gene transfer of cyclin-dependent kinase (CDK) inhibitors to suppress synovial cell cycling has shown efficacy in treating animal models rheumatoid arthritis. Endogenous CDK also modulate immune function via a CDK-independent pathway. Accordingly, systemic administration small molecules that inhibit may or not ameliorate To address this issue, alvocidib (flavopiridol), known be tolerated clinically for cancers, and newly synthesized CDK4/6-selective inhibitor were tested antiarthritic effects. In vitro, they inhibited proliferation human mouse fibroblasts without inducing apoptosis. vivo, treatment collagen-induced arthritis mice with suppressed hyperplasia joint destruction, whereas serum concentrations anti-collagen type II (CII) Abs proliferative responses CII maintained. Treatment was effective even when therapeutically administered. Treated developed after termination treatment. Thus, unimpaired. The same ameliorated induced by K/BxN lymphocyte-deficient mice. Similarly, the Both small-molecule suppressing lymphocyte function. two distinctive way, compared other immunosuppressive drugs.