title: Circadian timekeeping is disturbed in rheumatoid arthritis at molecular level.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  We conclude that the molecular machinery controlling the circadian rhythm is disturbed in RA patients.
authors: Department of Medicine, Institute of Clinical Medicine, University of Helsinki, Helsinki, Finland.
authors: Vesa-Petteri
authors: VP
authors: Kouri
authors: Juri
authors: J
authors: Olkkonen
authors: Emilia
authors: E
authors: Kaivosoja
authors: Mari
authors: M
authors: Ainola
authors: Juuso
authors: J
authors: Juhila
authors: Iiris
authors: I
authors: Hovatta
authors: Yrjö T
authors: YT
authors: Konttinen
authors: Jami
authors: J
authors: Mandelin
mesh_terms: D056930:ARNTL Transcription Factors / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D057906:Circadian Clocks / Q000235:genetics*; D005347:Fibroblasts / Q000378:metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D010003:Osteoarthritis / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D013583:Synovial Membrane / Q000378:metabolism
chemical_list: D056930:ARNTL Transcription Factors; D053583:Interleukin-1beta; D015850:Interleukin-6