Document Detail

Circadian timekeeping is disturbed in rheumatoid arthritis at molecular level.
MedLine Citation:
PMID:  23335987     Owner:  NLM     Status:  MEDLINE    
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.
Vesa-Petteri Kouri; Juri Olkkonen; Emilia Kaivosoja; Mari Ainola; Juuso Juhila; Iiris Hovatta; Yrjö T Konttinen; Jami Mandelin
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-01-15
Journal Detail:
Title:  PloS one     Volume:  8     ISSN:  1932-6203     ISO Abbreviation:  PLoS ONE     Publication Date:  2013  
Date Detail:
Created Date:  2013-01-21     Completed Date:  2013-06-27     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  101285081     Medline TA:  PLoS One     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e54049     Citation Subset:  IM    
Department of Medicine, Institute of Clinical Medicine, University of Helsinki, Helsinki, Finland.
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MeSH Terms
ARNTL Transcription Factors / metabolism
Arthritis, Rheumatoid / genetics*,  metabolism,  physiopathology*
Circadian Clocks / genetics*
Fibroblasts / metabolism
Gene Expression
Gene Expression Regulation
Interleukin-1beta / genetics,  metabolism
Interleukin-6 / genetics,  metabolism
Osteoarthritis / genetics,  metabolism
Protein Transport
Synovial Membrane / metabolism
Reg. No./Substance:
0/ARNTL Transcription Factors; 0/Interleukin-1beta; 0/Interleukin-6

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