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Circadian Timekeeping is Disturbed in Rheumatoid Arthritis at Molecular level

Show simple item record 2015-01-19T13:50:36Z 2015-07-29T08:42:34Z 2015-01-19T13:50:36Z 2015-07-29T08:42:34Z 2015-01-19T13:50:36Z
dc.title Circadian Timekeeping is Disturbed in Rheumatoid Arthritis at Molecular level en
ethesis.discipline Biochemistry en
ethesis.discipline Biokemia fi
ethesis.discipline Biokemi sv
ethesis.department Biomedicinska institutionen sv
ethesis.department Institute of Biomedicine en
ethesis.department Biolääketieteen laitos fi
ethesis.faculty Faculty of Medicine en
ethesis.faculty Medicinska fakulteten sv
ethesis.faculty Lääketieteellinen tiedekunta fi
ethesis.faculty.URI Helsingfors universitet sv University of Helsinki en Helsingin yliopisto fi
dct.creator Olkkonen, Juri
dct.issued 2015
dct.language.ISO639-2 eng
dct.abstract 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-a. 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-1b 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. en
dct.language en
ethesis.language English en
ethesis.language englanti fi
ethesis.language engelska sv
ethesis.supervisor Konttinen, Yrjö
ethesis.thesistype Syventävä tutkielma fi
dct.identifier.urn URN:NBN:fi:hulib-201507282611
dc.type.dcmitype Text
ethesis-internal.updated TRUE2

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