OBJECTIVE Circadian rhythms in cartilage homeostasis are hypothesized to temporally segregate and synchronize the activities of chondrocytes to different times of the day, and thus may provide an efficient mechanism by which articular cartilage can recover following physical activity. While the circadian clock is clearly involved in chondrocyte homeostasis in health and disease, it is unclear as to what roles it may play during early chondrogenesis. DESIGN The purpose of this study was to determine whether the rhythmic expression of the core circadian clock was detectable at the earliest stages of chondrocyte differentiation, and if so, whether a synchronized expression pattern of chondrogenic transcription factors and developing cartilage matrix constituents was present during cartilage formation. RESULTS Following serum shock, embryonic limb bud-derived chondrifying micromass cultures exhibited synchronized temporal expression patterns of core clock genes involved in the molecular circadian clock. We also observed that chondrogenic marker genes followed a circadian oscillatory pattern. Clock synchronization significantly enhanced cartilage matrix production and elevated SOX9, ACAN, and COL2A1 gene expression. The observed chondrogenesis-promoting effect of the serum shock was likely attributable to its synchronizing effect on the molecular clockwork, as co-application of small molecule modulators (longdaysin and KL001) abolished the stimulating effects on extracellular matrix production and chondrogenic marker gene expression. CONCLUSIONS Results from this study suggest that a functional molecular clockwork plays a positive role in tissue homeostasis and histogenesis during early chondrogenesis.

中文翻译：

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同步的生物钟可增强早期软骨形成。

目的 软骨稳态中的昼夜节律被假设为将软骨细胞的活动暂时隔离和同步到一天中的不同时间，因此可能提供一种有效的机制，通过该机制，关节软骨可以在身体活动后恢复。虽然生物钟显然与健康和疾病中的软骨细胞稳态有关，但尚不清楚它在早期软骨形成过程中可能发挥什么作用。设计 本研究的目的是确定在软骨细胞分化的早期是否可检测到核心生物钟的节律性表达，如果是，则在软骨过程中是否存在软骨形成转录因子和发育中的软骨基质成分的同步表达模式形成。结果血清休克后，胚胎肢芽衍生的软骨化微团培养物表现出参与分子生物钟的核心时钟基因的同步时间表达模式。我们还观察到软骨形成标记基因遵循昼夜节律振荡模式。时钟同步显着增强了软骨基质的产生并提高了 SOX9、ACAN 和 COL2A1 基因的表达。观察到的血清休克的软骨形成促进作用可能归因于其对分子发条的同步作用，因为小分子调节剂（longdaysin 和 KL001）的共同应用消除了对细胞外基质产生和软骨形成标记基因表达的刺激作用。