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

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.

Circadian clocks drive ~24 hour rhythms in nearly all aspects of mammalian physiology and behaviour. Changes of circadian rhythms during ageing are now thought to underpin many of the age-associated pathologies. Our preliminary data demonstrates cell autonomous circadian clocks in the mouse cartilage tissue and human chondrocytes. Importantly, our cartilage circadian transcriptome profiling data strongly implicate circadian clocks as regulators of key genes involved in cartilage homeostasis, in chondrocyte survival and with potential importance in osteoarthritis (OA) pathogenesis. In this proposal, we will combine a novel transgenic mouse model with chondrocyte-specific ablation of circadian clock, with an experimental mouse OA model and with supporting human chondrocyte experiments to address the following key questions: 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? These studies may identify novel strategies that target clock components or circadian rhythm to restore cartilage tissue homeostasis and prevent/delay arthritic disease onset. Such knowledge may also improve current treatments for joint diseases, for instance, by timing drug delivery to increase efficacy and reduce toxicity.

Osteoarthritis (OA) is the most prevalent age-related joint disease, causing pain and stiffness in joints and affecting at least 8 million people in the UK. There is currently no cure for this condition, and at later stages of OA, joint replacement becomes the viable option. The significant disability associated with OA impairs the quality of life, making OA a serious medical concern and economic burden. The greying of the population and the ever-increasing demands of our modern 24/7 society frequently lead to disruptions of circadian rhythms generated by our body clocks, which consequently increase risks of developing various diseases, including obesity, diabetes and cardiovascular diseases. This project will combine studies in a novel transgenic mouse model with chondrocyte-specific clock disruption, human chondrocytes in culture, and an experimental model of OA, in order to gain significant biological insights into the function of cartilage clocks in tissue homeostasis and disease susceptibility. Our research may identify novel therapeutic strategies for joint diseases, or improve the efficacy of current treatments, therefore has an enormous potential for improving health and quality of life. Moreover, the functional significance of circadian rhythms in OA will emphasize the importance of maintaining robust circadian rhythms through healthy life styles, which will have a long lasting impact on the health and well being of the ageing population.

Who will benefit from this research?
This project will initially benefit a wide range of researchers, as described in the Academic Beneficiaries section. The pathways identified by this project that link circadian clocks to chondrocyte biology(such as REV-ERBa and RORa which belong to the nuclear hormone receptors super family) are likely to also benefit pharmaceutical industries. In fact, GSK and Pfizer have already started investigating the possibilities of targeting NHRs (PPARa/g and LXR) for arthritic diseases. Further mechanistic insights into how the clock related NHRs regulate chondrocyte pathways will greatly help refine the drug targets and design principles in this regard. Moreover, our studies indicate that many of the genes involved in cartilage homeostasis, in chondrocyte survival and with potential importance in OA pathogenesis are rhythmically expressed, including matrix-degrading enzymes, catabolic/anabolic signalling molecules, and one of the OA susceptibility genes (GNL3) newly identified by the arcOGEN GWAS study. The rhythmic nature of these targets call for novel treatment strategies for joint diseases, which take into accounts the time-of-day effect, i.e., chronopharmacology or chronotherapy. On the other hand, the quest for prognostic biomarkers of joint diseases also has to consider their potential daily variations. Finally, elucidating the roles of circadian rhythms in cartilage physiology and OA susceptibility will have profound impacts on public understanding of rhythm disruptions and disease risks. We expect that the outcomes will be media worthy and be of interest to the OA sufferers, health care professionals working with OA patients, the general public and the elderly population.

How will they benefit from this research?
Outcomes from this research will be published expeditiously in high-profile journals that have open access options. Results will also be disseminated by participating in conferences, seminars, public lectures and media reports. Key findings will also be featured on the PI and Co-PI's group web pages. In the long term, it may be possible to translate the outcomes into novel medical practice that aims at ameliorating arthritic diseases, e.g., by targeting circadian rhythms/clock components, or timed delivery of current therapeutic medications. As such, this project holds the potential of a profound long-term impact on health and quality of life, with a long lasting economic and social impact.