How do circadian clocks in chondrocytes contribute to cartilage function in health and disease

本研究旨在探讨关节软骨生物钟的分子/细胞机制及其在骨性关节炎(OA)损伤发展和严重程度中的作用。生物钟(大约一天)是我们体内的内源性计时器，负责产生24小时的行为和生理节奏。高龄、倒班工作或时差造成的昼夜节律紊乱会对身体功能和疾病风险产生严重影响。通过在培养皿中培养软骨细胞(软骨中唯一的细胞类型)，分离软骨碎片，以及在时钟破坏的小鼠膝关节中模拟骨性关节炎的外科手术，我们有望解开：1)软骨中哪些节律基因依赖于局部软骨细胞时钟来维持其昼夜节律表达模式？2)我们能否将软骨昼夜节律蛋白作为改变软骨细胞基因表达的新方法？3)时钟机制的特定组件的变化是否会导致早期骨性关节炎的发生，或者使小鼠更容易受到手术损伤引起的骨性关节炎的影响？该项目将产生新的数据和知识，这将使从事昼夜生物学、软骨细胞生物学、衰老和关节疾病工作的研究人员受益。这也可能使制药行业受益，他们有兴趣开发针对关节炎疾病的新方法。结果将促进我们对昼夜节律在关节软骨健康状态中所起作用的理解，因此对普通公众也将是有价值的。

This research focuses on the molecular/cellular mechanisms of biological clocks in the joint cartilage and their contributions to the development and severity of damage in osteoarthritis (OA). Circadian (about a day) clocks are endogenous time pieces in our bodies that are responsible for generating 24 hour rhythms in behaviour and physiology. Disruptions of circadian rhythms by advanced age, shift work or jet lag can have severe impacts on body functions and disease risks. By culturing chondrocyte cells (the only cell type in cartilage) in petri dishes, isolating cartilage pieces, and a surgical operation which mimics OA in clock disrupted mouse knee joint, we expect to unravel: 1) Which rhythmic genes in cartilage rely on the local chondrocyte clock to maintain their circadian pattern of expression? 2) Can we target cartilage circadian clock proteins as a novel approach to alter chondrocyte gene expression? 3) Do alterations in specific components of the clock mechanism cause early onset OA, or leave mice more susceptible to surgical injury-induced OA? This project will generate new data and knowledge that will benefit researchers working on circadian biology, chondrocyte biology, ageing and joint diseases. It is also likely to benefit pharmaceutical industries who are interested in developing new approaches to targeting arthritic diseases. Outcomes will advance our understanding of the role circadian rhythms play in the healthy state of the joint cartilage, so will also be of value to the general public.