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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cartilage, Articular / metabolism
  • Cartilage, Articular / pathology
  • Cells, Cultured
  • Chondrocytes / metabolism*
  • Circadian Clocks / genetics*
  • Cytokines / biosynthesis
  • Cytokines / genetics*
  • DNA / genetics*
  • Disease Models, Animal
  • Gene Expression Regulation*
  • Mice
  • Mice, Transgenic
  • NF-kappa B / biosynthesis
  • NF-kappa B / genetics*
  • Osteoarthritis / genetics*
  • Osteoarthritis / metabolism
  • Osteoarthritis / pathology
  • Reverse Transcriptase Polymerase Chain Reaction


  • Cytokines
  • NF-kappa B
  • DNA