Cell cycle and diseases

关节内基因转移细胞周期蛋白依赖性激酶抑制物(CDKI)抑制滑膜细胞周期已在治疗类风湿性关节炎(RA)动物模型中显示出有效性。CDKI还通过CDK非依赖性途径调节免疫功能。因此，全身给药的小分子抑制。CDK可能对关节炎有改善作用。为了解决这个问题，我们测试了临床上可以耐受的治疗癌症的阿沃西地布，以及一种新合成的CDK4/6选择性抑制剂，以观察其抗关节炎作用。在体外，它们抑制人和小鼠滑膜成纤维细胞的增殖，而不诱导细胞凋亡。在体内，阿沃西地布治疗胶原性关节炎(CIA)小鼠可抑制滑膜增生和关节破坏，同时维持血清抗II型胶原抗体(CLL)浓度和对CLL的增殖反应。即使在治疗性的情况下，治疗也是有效的。接受治疗的小鼠在终止治疗后出现关节炎。因此，对CLL的免疫反应没有受到损害。同样的治疗方法可以改善K/BxN血清转移给淋巴细胞缺陷小鼠所引起的关节炎。同样，CDK4/6选择性抑制剂抑制CIA。两种小分子(Sm)CDK抑制剂都能有效地治疗RA动物模型，而不是通过抑制淋巴细胞功能。我们认为，smCDK抑制剂有望成为一类新型的抗风湿药物，可以抑制风湿病发病的不同阶段。

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