Circadian timekeeping is disturbed in rheumatoid arthritis at molecular level

PLoS One. 2013;8(1):e54049. doi: 10.1371/journal.pone.0054049. Epub 2013 Jan 15.


Introduction: Patients with rheumatoid arthritis (RA) have disturbances in the hypothalamic-pituitary-adrenal (HPA) axis. These are reflected in altered circadian rhythm of circulating serum cortisol, melatonin and IL-6 levels and in chronic fatigue. We hypothesized that the molecular machinery responsible for the circadian timekeeping is perturbed in RA. The aim of this study was to investigate the expression of circadian clock in RA.

Methods: Gene expression of thirteen clock genes was analyzed in the synovial membrane of RA and control osteoarthritis (OA) patients. BMAL1 protein was detected using immunohistochemistry. Cell autonomous clock oscillation was started in RA and OA synovial fibroblasts using serum shock. The effect of pro-inflammatory stimulus on clock gene expression in synovial fibroblasts was studied using IL-6 and TNF-α.

Results: Gene expression analysis disclosed disconcerted circadian timekeeping and immunohistochemistry revealed strong cytoplasmic localization of BMAL1 in RA patients. Perturbed circadian timekeeping is at least in part inflammation independent and cell autonomous, because RA synovial fibroblasts display altered circadian expression of several clock components, and perturbed circadian production of IL-6 and IL-1β after clock resetting. However, inflammatory stimulus disturbs the rhythm in cultured fibroblasts. Throughout the experiments ARNTL2 and NPAS2 appeared to be the most affected clock genes in human immune-inflammatory conditions.

Conclusion: We conclude that the molecular machinery controlling the circadian rhythm is disturbed in RA patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ARNTL Transcription Factors / metabolism
  • Arthritis, Rheumatoid / genetics*
  • Arthritis, Rheumatoid / metabolism
  • Arthritis, Rheumatoid / physiopathology*
  • Circadian Clocks / genetics*
  • Fibroblasts / metabolism
  • Gene Expression
  • Gene Expression Regulation
  • Humans
  • Interleukin-1beta / genetics
  • Interleukin-1beta / metabolism
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism
  • Osteoarthritis / genetics
  • Osteoarthritis / metabolism
  • Protein Transport
  • Synovial Membrane / metabolism


  • ARNTL Transcription Factors
  • Interleukin-1beta
  • Interleukin-6

Grant support

This work was supported by the Academy of Finland, Finnish Society for Rheumatology, Finska Läkaresällskapet, ORTON Orthopaedic Hospital of the ORTON Foundation, Danish Council for Strategic Research, Scandinavian Rheumatology Research Foundation, Paulo Foundation, University of Helsinki, National Graduate School of Musculoskeletal Disorders and Biomaterials and Orion-Farmos Research Fund. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.