The intervertebral disc contains intrinsic circadian clocks that are regulated by age and cytokines and linked to degeneration.
The intervertebral disc contains intrinsic circadian clocks that are regulated by age and cytokines and linked to degeneration.
复制标题
DOI：
10.1136/annrheumdis-2016-209428
复制
发表时间：
2017-03
影响因子：
27.4
通讯作者：
Meng QJ
中科院分区：
文献类型：
--
作者：
Dudek M;Yang N;Ruckshanthi JP;Williams J;Borysiewicz E;Wang P;Adamson A;Li J;Bateman JF;White MR;Boot-Handford RP;Hoyland JA;Meng QJ
生物钟是内部计时机制，以特定于组织的方式驱动∼24小时节律。间盘生理(IVD)的许多方面显示出明显的昼夜节律。然而，目前尚不清楚IVD组织中是否包含有功能的生物钟，如果是，它们的失调如何与IVD的退变有关。用生物荧光光子计数和成像技术实时监测了体外IVD外植体(来自PER2：：LUC报告基因小鼠)和人视盘细胞(含PER2：：LUC报告基因的慢病毒转导)中时钟基因的动态变化。用RNAseq和定量逆转录聚合酶链式反应(QRT-PCR)研究时间基因表达的变化。在组织特异性缺失核心时钟基因BMal1的小鼠模型中，通过组织学评估了IVD的病理。在这里，我们展示了在小鼠IVD组织和人类椎间盘细胞中存在昼夜节律。在小鼠中，这种节律随着年龄的增长而减弱，可以通过白细胞介素1β治疗而被取消，但不能通过肿瘤坏死因子α治疗。时间序列RNAseq揭示了607个基因的24小时表达模式，代表了IVD生理学中的几个基本途径。在其椎间盘细胞中有条件地敲除BMal1的小鼠表现出与年龄相关的IVD退化。我们已经在小鼠和人类的IVD细胞中建立了自主的昼夜节律时钟，它对年龄和细胞因子做出反应，并控制参与IVD动态平衡的关键通路。小鼠IVD分子时钟的遗传破坏易导致IVD退化。这些结果支持这样一个概念，即昼夜节律的紊乱可能是退行性IVD疾病和下腰痛的危险因素。
The circadian clocks are internal timing mechanisms that drive ∼24-hour rhythms in a tissue-specific manner. Many aspects of the physiology of the intervertebral disc (IVD) show clear diurnal rhythms. However, it is unknown whether IVD tissue contains functional circadian clocks and if so, how their dysregulation is implicated in IVD degeneration. Clock gene dynamics in ex vivo IVD explants (from PER2:: luciferase (LUC) reporter mice) and human disc cells (transduced with lentivirus containing Per2::luc reporters) were monitored in real time by bioluminescence photon counting and imaging. Temporal gene expression changes were studied by RNAseq and quantitative reverse transcription (qRT)-PCR. IVD pathology was evaluated by histology in a mouse model with tissue-specific deletion of the core clock gene Bmal1. Here we show the existence of the circadian rhythm in mouse IVD tissue and human disc cells. This rhythm is dampened with ageing in mice and can be abolished by treatment with interleukin-1β but not tumour necrosis factor α. Time-series RNAseq revealed 607 genes with 24-hour patterns of expression representing several essential pathways in IVD physiology. Mice with conditional knockout of Bmal1 in their disc cells demonstrated age-related degeneration of IVDs. We have established autonomous circadian clocks in mouse and human IVD cells which respond to age and cytokines, and control key pathways involved in the homeostasis of IVDs. Genetic disruption to the mouse IVD molecular clock predisposes to IVD degeneration. These results support the concept that disruptions to circadian rhythms may be a risk factor for degenerative IVD disease and low back pain.