Disruption of circadian rhythm aggravates experimental arthritis: study in cry gene-knockout mice.

哺乳动物的时钟基因，Per和Cry，生理上调节着昼夜节律。我们发现，小鼠实验性关节炎损害了PER和Cry的节律性表达，Cry的缺失进一步加剧了关节炎。在人类类风湿关节炎(RA)中，WeE-1激酶和反式激活因子c-Fos/AP-1表达上调，而WeE-1是Cry-1/2缺陷小鼠细胞周期调节因子中唯一上调的分子，而Cry-1/2缺陷小鼠的脾T细胞被激活，c-Fos/AP-1、Wee-1、炎性细胞因子包括肿瘤坏死因子-a、IL-1b、IL-6和基质降解基质金属蛋白酶-3均升高。特别是，Cry反式激活了促炎细胞因子TNF-a。因此，生物钟调节人类的健康和疾病，特别是关节炎。

Mammalian clock genes, Per and Cry, physiologically regulate circadian rhythm. We show that experimental arthritis in mice impairs rhythmic expression of Per and Cry, and deletion of Cry further aggravates arthritis to maximal levels. While Wee-1 kinase and c-Fos/ AP-1, a transactivator of Wee-1, are up-regulated in human rheumatoid arthritis (RA), and Wee-1 is the sole molecule up-regulated among cell cycle regulators in Cry-1/2 deficient mice, the splenic T cells of Cry-1/2 deficient mice were activated, and the molecules playing essential roles in arthritis such as c-Fos/AP-1, Wee-1, inflammatory cytokines including TNF-a, IL-lb and IL-6, and matrix-degrading MMP-3 were all increased. In particular, Cry transactivated pro-inflammatory cytokine TNF-a. Thus, biological clock modulates human health and disease, in particular, arthritis