title: Mammalian clock gene Cryptochrome regulates arthritis via proinflammatory cytokine TNF-alpha.
abstract: The mammalian clock genes, Period and Cryptochrome (Cry), regulate circadian rhythm. We show that circadian rhythmicity and rhythmic expression of Period in the nuclei of inflammatory synovial cells and spleen cells are disturbed in mouse models of experimental arthritis. Expressions of other clock genes, Bmal1 and Dbp, are also disturbed in spleen cells by arthritis induction. Deletion of Cry1 and Cry2 results in an increase in the number of activated CD3(+) CD69(+) T cells and a higher production of TNF-alpha from spleen cells. When arthritis is induced, Cry1(-/-)Cry2(-/-) mice develop maximal exacerbation of joint swelling, and upregulation of essential mediators of arthritis, including TNF-alpha, IL-1beta and IL-6, and matrix metalloproteinase-3. Wee-1 kinase is solely upregulated in Cry1(-/-)Cry2(-/-) mice, in line with upregulation of c-Fos and Wee-1 kinase in human rheumatoid arthritis. The treatment with anti-TNF-alpha Ab significantly reduced the severity and halted the progression of the arthritis of Cry1(-/-)Cry2(-/-) mice and vice versa, ectopic expression of Cry1 in the mouse embryonic fibroblast from Cry1(-/-)Cry2(-/-) mice significantly reduced the trans activation of TNF-alpha gene. Thus, the biological clock and arthritis influence each other, and this interplay can influence human health and disease.
authors.affiliation: Department of Biophysics, Graduate School of Health Science, Kobe University, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Hashiramoto
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamane
authors.forename: Ken
authors.initials: K
authors.lastname: Tsumiyama
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Yoshida
authors.forename: Koichiro
authors.initials: K
authors.lastname: Komai
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamada
authors.forename: Fumiyoshi
authors.initials: F
authors.lastname: Yamazaki
authors.forename: Masao
authors.initials: M
authors.lastname: Doi
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Okamura
authors.forename: Shunichi
authors.initials: S
authors.lastname: Shiozawa
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology*; D056926:CLOCK Proteins / Q000096:biosynthesis / Q000235:genetics; D002940:Circadian Rhythm / Q000235:genetics*; D056931:Cryptochromes / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D005260:Female; D018836:Inflammation Mediators / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
chemical_list: C538964:Cry1 protein, mouse; C538967:Cry2 protein, mouse; D056931:Cryptochromes; D018836:Inflammation Mediators; D014409:Tumor Necrosis Factor-alpha; D056926:CLOCK Proteins