Circadian timekeeping is disturbed in rheumatoid arthritis at molecular level.
Circadian timekeeping is disturbed in rheumatoid arthritis at molecular level.
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DOI：
10.1371/journal.pone.0054049
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Mandelin J
中科院分区：
文献类型：
--
作者：
Kouri VP;Olkkonen J;Kaivosoja E;Ainola M;Juhila J;Hovatta I;Konttinen YT;Mandelin J
类风湿关节炎(RA)患者存在下丘脑-垂体-肾上腺(HPA)轴的紊乱。这些反映在循环血清皮质醇、褪黑素和IL-6水平的昼夜节律改变以及慢性疲劳上。我们假设负责昼夜节律的分子机制在类风湿性关节炎中受到干扰。本研究的目的是探讨生物钟在类风湿关节炎中的表达。分析了13个Clock基因在类风湿关节炎(RA)和对照骨关节炎(OA)患者滑膜中的基因表达。免疫组织化学方法检测BMal1蛋白的表达。在RA和OA滑膜成纤维细胞中，使用血清休克启动细胞自主时钟振荡。应用IL-6和肿瘤坏死因子-α检测促炎刺激对滑膜成纤维细胞时钟基因表达的影响。基因表达分析显示RA患者BMAL1的昼夜节律紊乱，免疫组织化学显示BMAL1在细胞质中有较强的定位。紊乱的昼夜节律计时至少在一定程度上是炎症非依赖性和细胞自主性的，因为RA滑膜成纤维细胞表现出几个时钟成分的昼夜节律表达改变，并在时钟重置后扰乱了IL-6和IL-1β的昼夜节律产生。然而，炎症刺激扰乱了培养的成纤维细胞的节律。在整个实验中，ARNTL2和NPAS2似乎是人类免疫炎症条件下受影响最大的时钟基因。我们的结论是，控制昼夜节律的分子机制在RA患者中受到干扰。
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. 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. 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. We conclude that the molecular machinery controlling the circadian rhythm is disturbed in RA patients.
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影响因子：
64.5
作者：
Ivanov, Ivaylo I.;McKenzie, Brent S.;Littman, Dan R.
通讯作者：
Littman, Dan R.
DOI：
10.1002/art.21450
发表时间：
2005-10-15
期刊：
ARTHRITIS & RHEUMATISM-ARTHRITIS CARE & RESEARCH
影响因子：
--
作者：
Hewlett, S;Cockshott, Z;Hehir, M
通讯作者：
Hehir, M
影响因子：
64.5
作者：
Balsalobre, A;Damiola, F;Schibler, U
通讯作者：
Schibler, U
DOI：
10.1007/bf02190343
发表时间：
1992-09-01
影响因子：
4.7
作者：
GUDEWILL, S;POLLMACHER, T;HOLSBOER, F
通讯作者：
HOLSBOER, F
影响因子：
56.9
作者：
Balsalobre, A;Brown, SA;Schibler, U
通讯作者：
Schibler, U