June 16, 2009 The genes that regulate human circadian rhythm, or 'the body clock', are significantly disturbed in individuals with arthritis, according to the results of a new study presented today at EULAR 2009, the Annual Congress of the European League Against Rheumatism in Copenhagen, Denmark. Notably, a specific genetic pathway has been identified as responsible for interactions between the genes that regulate the body clock and those that may worsen symptoms of arthritis.
In a sample of 200 rheumatoid arthritis (RA) patients, sleep was determined to be significantly disturbed in over 61%, as determined by a Pittsburg Sleep Quality Index (PSQI) score of >5 (the PSQI global score was 8.55 ±4.69). These values were shown to correlate with several measures of arthritis disease activity, including levels of c-reactive protein, swollen joint count and DAS28*.
A further element of the study looked into the expression patterns of certain genes in mice with arthritis. Here, researchers identified a novel biochemical pathway in which the circadian regulatory gene CRY was found to up-regulate expression of a gene which promotes the activation of TNF-alpha (tumour necrosis factor-alpha, a pro-inflammatory cytokine used by the body to boost the immune system) by two fold, when comparing mice with the CRY gene removed to those with a normal copy of the gene.
Professor Shunichi Shiozawa of Kobe University Graduate School of Medicine and University Hospital, Japan, who led the research said: "Our study has shown that arthritis interferes with the genetics behind an individual's circadian rhythm and, specifically, that certain body clock genes may play a part in the activation of TNF-alpha, a signaling molecule that has an important role in the inflammation commonly seen in a number of rheumatologic conditions. The identification of this curious pathway may help to explain the 24-hour symptom cycle seen by many patients who experience worsening of joint pain and stiffness in the mornings, and lead to further research into new approaches for improving daily quality of life."
RA patients who participated in the study were attending the Kakogawa Konan Hospital and Kobe University Hospitals. Experimental arthritis was induced in mice with the CRY gene removed. Expression of the genes responsible for regulation of the human body clock were determined by immunohistochemistry and quantitative Polymerase Chain Reaction. TNF-alpha levels were measured by ELISA, and transactivation of TNF-alpha gene was examined by reporter assay.
* DAS28 (Disease Activity Score) is an index used by physicians to measure how active an individual's RA is. It assesses number of tender and swollen joints (out of a total of 28), the erythrocyte sedimentation rate (ESR, a blood marker of inflammation), and the patient's 'global assessment of global health'. A higher score indicates more active disease.
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