The circadian clock in murine chondrocytes regulates genes controlling key aspects of cartilage homeostasis.
The circadian clock in murine chondrocytes regulates genes controlling key aspects of cartilage homeostasis.
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DOI：
10.1002/art.38035
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发表时间：
2013-09
影响因子：
--
通讯作者：
Meng, Qing-Jun
中科院分区：
文献类型：
--
作者：
Gossan, Nicole;Zeef, Leo;Hensman, James;Hughes, Alun;Bateman, John F.;Rowley, Lynn;Little, Christopher B.;Piggins, Hugh D.;Rattray, Magnus;Boot-Handford, Raymond P.;Meng, Qing-Jun
目的研究小鼠骨关节炎（OA）软骨组织的生物钟特征，筛选组织特异性生物钟靶基因，并探讨生物钟在衰老和软骨退变过程中的变化。方法将PER2：：luc基因导入老年小鼠和青年小鼠的腕关节组织中，采用实时荧光法检测PER2：：luc基因的生物钟特性。在小鼠软骨组织上进行时间序列微阵列以鉴定以昼夜节律方式表达的基因。使用小鼠组织、原代软骨细胞和人软骨细胞系，通过定量逆转录聚合酶链反应证实了节律基因。实验OA诱导小鼠的内侧半月板（DMM）的不稳定，关节软骨样品进行显微解剖和微阵列分析。结果发现小鼠软骨组织和人软骨细胞系含有内在的分子生物钟。软骨生物钟可以通过温度信号进行重置，而昼夜节律周期是温度补偿的。PER 2：：luc生物发光表明，老年小鼠软骨中的昼夜节律振荡幅度显著较低。对小鼠组织的时间序列微阵列分析确定了软骨中的第一个昼夜节律转录组，揭示了615个基因（占表达基因的3.9%）显示出昼夜节律表达模式。这包括参与软骨稳态和存活的基因，以及在OA发病机制中具有潜在重要性的基因。在OA的DMM小鼠模型中，几个时钟基因在软骨退化的早期阶段被破坏。结论这些结果揭示了软骨细胞中自主的生物钟，可能与软骨生物学和病理学的关键方面有关。因此，昼夜节律中断（例如，在老化过程中）可能损害组织稳态并增加对关节损伤或疾病的易感性。
ObjectiveTo characterize the circadian clock in murine cartilage tissue and identify tissue-specific clock target genes, and to investigate whether the circadian clock changes during aging or during cartilage degeneration using an experimental mouse model of osteoarthritis (OA). MethodsCartilage explants were obtained from aged and young adult mice after transduction with the circadian clock fusion protein reporter PER2::luc, and real-time bioluminescence recordings were used to characterize the properties of the clock. Time-series microarrays were performed on mouse cartilage tissue to identify genes expressed in a circadian manner. Rhythmic genes were confirmed by quantitative reverse transcription–polymerase chain reaction using mouse tissue, primary chondrocytes, and a human chondrocyte cell line. Experimental OA was induced in mice by destabilization of the medial meniscus (DMM), and articular cartilage samples were microdissected and subjected to microarray analysis. ResultsMouse cartilage tissue and a human chondrocyte cell line were found to contain intrinsic molecular circadian clocks. The cartilage clock could be reset by temperature signals, while the circadian period was temperature compensated. PER2::luc bioluminescence demonstrated that circadian oscillations were significantly lower in amplitude in cartilage from aged mice. Time-series microarray analyses of the mouse tissue identified the first circadian transcriptome in cartilage, revealing that 615 genes (∼3.9% of the expressed genes) displayed a circadian pattern of expression. This included genes involved in cartilage homeostasis and survival, as well as genes with potential importance in the pathogenesis of OA. Several clock genes were disrupted in the early stages of cartilage degeneration in the DMM mouse model of OA. ConclusionThese results reveal an autonomous circadian clock in chondrocytes that can be implicated in key aspects of cartilage biology and pathology. Consequently, circadian disruption (e.g., during aging) may compromise tissue homeostasis and increase susceptibility to joint damage or disease.
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影响因子：
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作者：
Feillet, Celine A.;Albrecht, Urs;Challet, Etienne
通讯作者：
Challet, Etienne
影响因子：
3.5
作者：
Hughes ME;Hogenesch JB;Kornacker K
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