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

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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