期刊
OSTEOARTHRITIS AND CARTILAGE
卷 23, 期 11, 页码 1981-1988出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.joca.2015.02.020
关键词
Circadian clock; Cartilage; Cytokine; Inflammation; Osteoarthritis
资金
- Medical Research Council (MRC) Career Development Award [G0900414]
- MRC grant [MR/K019392/1]
- BBSRC SABR [BB/F005938/2]
- sLOLA [BB/K003097/1]
- MRC [MR/K015885/1]
- EU [FP7/305564]
- National Natural Science Foundation of China [81450044, 81171253, 31200889]
- BBSRC [BB/F005938/2, BB/F005938/1, BB/K003097/1] Funding Source: UKRI
- MRC [MR/K019392/1, G0900414, MR/M008908/1, MC_U105170643, MR/K015885/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/F005938/1, 1627358, 1362568, BB/K003097/1, BB/F005938/2] Funding Source: researchfish
- Medical Research Council [MC_U105170643, MR/K019392/1, MR/K015885/1, G0900414, MR/M008908/1] Funding Source: researchfish
- Versus Arthritis [20875] Funding Source: researchfish
Objective: To define how the catabolic cytokines (Interleukin 1 (IL-1) and tumor necrosis factor alpha (TNF alpha)) affect the circadian clock mechanism and the expression of clock-controlled catabolic genes within cartilage, and to identify the downstream pathways linking the cytokines to the molecular clock within chondrocytes. Methods: Ex vivo cartilage explants were isolated from the Cry1-luc or PER2::LUC clock reporter mice. Clock gene dynamics were monitored in real-time by bioluminescence photon counting. Gene expression changes were studied by qRT-PCR. Functional luc assays were used to study the function of the core Clock/BMAL1 complex in SW-1353 cells. NF kappa B pathway inhibitor and fluorescence live-imaging of cartilage were performed to study the underlying mechanisms. Results: Exposure to IL-1 beta severely disrupted circadian gene expression rhythms in cartilage. This effect was reversed by an anti-inflammatory drug dexamethasone, but not by other clock synchronizing agents. Circadian disruption mediated by IL-1 beta was accompanied by disregulated expression of endogenous clock genes and clock-controlled catabolic pathways. Mechanistically, NF kappa B signalling was involved in the effect of IL-1 beta on the cartilage clock in part through functional interference with the core Clock/BMAL1 complex. In contrast, TNF alpha had little impact on the circadian rhythm and clock gene expression in cartilage. Conclusion: In our experimental system (young healthy mouse cartilage), we demonstrate that IL-1 beta (but not TNF alpha) abolishes circadian rhythms in Cry1-luc and PER2::LUC gene expression. These data implicate disruption of the chondrocyte clock as a novel aspect of the catabolic responses of cartilage to proinflammatory cytokines, and provide an additional mechanism for how chronic joint inflammation may contribute to osteoarthritis (OA). (C) 2015 The Authors. Published by Elsevier Ltd and Osteoarthritis Research Society International.
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