Format

Send to

Choose Destination
Osteoarthritis Cartilage. 2015 Nov;23(11):1981-8. doi: 10.1016/j.joca.2015.02.020.

Catabolic cytokines disrupt the circadian clock and the expression of clock-controlled genes in cartilage via an NFкB-dependent pathway.

Author information

1
Faculty of Life Sciences, University of Manchester, A.V. Hill Building, Oxford Road, Manchester, M13 9PT, UK.
2
Faculty of Life Sciences, University of Manchester, A.V. Hill Building, Oxford Road, Manchester, M13 9PT, UK; Department of Chronopharmacology, School of Pharmacy, Taishan Medical University, Chang Cheng Road, Shandong, 271016, PR China.
3
MRC Laboratory of Molecular Biology, Neurobiology Division, Francis Crick Ave, Cambridge, CB2 0QH, UK.
4
Murdoch Childrens Research Institute, Parkville, Victoria, 3052, Australia.
5
Wellcome Trust Centre for Cell Matrix Research, University of Manchester, Oxford Road, Manchester, M13 9PT, UK.
6
Faculty of Life Sciences, University of Manchester, A.V. Hill Building, Oxford Road, Manchester, M13 9PT, UK. Electronic address: qing-jun.meng@manchester.ac.uk.

Abstract

OBJECTIVE:

To define how the catabolic cytokines (Interleukin 1 (IL-1) and tumor necrosis factor alpha (TNFα)) 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. NFкB pathway inhibitor and fluorescence live-imaging of cartilage were performed to study the underlying mechanisms.

RESULTS:

Exposure to IL-1β 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-1β was accompanied by disregulated expression of endogenous clock genes and clock-controlled catabolic pathways. Mechanistically, NFкB signalling was involved in the effect of IL-1β on the cartilage clock in part through functional interference with the core Clock/BMAL1 complex. In contrast, TNFα 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-1β (but not TNFα) 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 pro-inflammatory cytokines, and provide an additional mechanism for how chronic joint inflammation may contribute to osteoarthritis (OA).

KEYWORDS:

Cartilage; Circadian clock; Cytokine; Inflammation; Osteoarthritis

PMID:
26521744
PMCID:
PMC4638193
DOI:
10.1016/j.joca.2015.02.020
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center