New treatment of rheumatoid arthritis

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，全身应用抑制CDK的小分子可能会改善关节炎。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)可抑制滑膜增生和关节破坏，同时维持血清中抗II型胶原(CII)抗体的浓度。接受治疗的小鼠在终止治疗后出现关节炎。因此，对CII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，即使在临床疾病发作后给予也是如此。两种小分子(Sm)CDK抑制剂均通过抑制滑膜细胞生长而不是免疫功能而有效地治疗类风湿关节炎动物模型。我们认为，smCDK抑制剂有望成为一类新的抗风湿药物，抑制类风湿发病的不同阶段。

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 synovial fibroblasts without inducing apoptosis. In vivo, treatment of collagen-induced arthritis (CIA) with alvocidib suppressed synovial hyperplasia and joint destruction while serum concentrations of anti- type II collagen (CII) antibodies were maintained. 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 CIA, even when administered after onset of clinical disease. Both small molecule (sm) CDK inhibitors were effective in treating animal models of RA by suppressing synovial cell growth but not immune function. We believe that smCDK inhibitors hold promise as a new class of anti-rheumatic drugs that inhibit a distinct phase of rheumatoid pathogenesis.