Developing temperature and osmolarity based therapeutic approaches to modulate circadian rhythm in degenerative intervertebral disc and promote repair

Low back pain (LBP), caused by degeneration of the soft tissue called intervertebral disc in the spine, is amongst the most prevalent spinal diseases. It affects millions of individuals worldwide, causing severe pain and loss of mobility, with currently no long-term cure. Ageing is a major risk factor. However, we do not fully understand why age increases susceptibility to disc degeneration and LBP. Body clocks are responsible for generating 24 hour (circadian) rhythms in behaviour and physiology. Rhythm disruptions by ageing or shift work can significantly increase disease risks. Crucially, our group, for the first time, have discovered a functional body clock in the intervertebral disc. This peripheral body clock weakens with age and its disruption leads to tissue damage characteristic of disc degeneration, such as bone-like changes within the soft tissue. This project will establish how body clock disruption leads to disc degeneration and bone-like changes in the spinal disc. We will also explore the therapeutic potential of targeting the body clocks using drugs or temperature in order to restore tissue function and promote repair.
Specifically, we will use our novel disc "clockless" mouse model, intervertebral disc explant culture and patient samples to address the following specific questions: 1), How dysregulation of the 24 hour rhythm leads to bone-like changes in the spinal disc and can we modulate this process by body clock-acting drugs? 2), Can we utilise periodic heat pulses to boost the daily rhythm in the spine as a new means to enhance tissue repair? 3), How the osmolarity cycle entrains the IVD circadian rhythm and can we use pharmacological compounds as mimetics to modulate circadian rhythms in the IVD?
This research builds on our recent MRC-funded novel discoveries and holds strong potential to identify new therapeutic strategies for low back pain and therefore has an enormous potential for improving health and quality of life. Moreover, our findings emphasize the importance of maintaining robust body clocks through healthy life styles, which will have a long lasting impact on the health and well-being of the ageing population. This is particularly important because the greying of the population and the ever-increasing demands of our modern 24/7 society frequently disrupt our body clocks which can significantly increase risk of many diseases, including low back pain.

Circadian clocks drive ~24 hour rhythms in nearly all aspects of our physiology and behaviour. Changes of circadian rhythms during ageing underpin many of the age-associated pathologies. Low back pain is amongst the most prevalent spinal diseases associated with increasing age. It causes severe pain and loss of mobility, with currently no long-term cure. Progressive degeneration of the intervertebral disc (IVD) tissue is a major contributing factor. However, how susceptibility to IVD degeneration and LBP increases with age is poorly understood. Funded by the MRC, our ground-breaking work has demonstrated cell autonomous circadian clocks in mouse and human IVD. The IVD circadian clock controls rhythmic expression of >600 genes, many are known key players in IVD tissue homeostasis. Genetic disruption of the intrinsic IVD clock in mice leads to tissue damage characteristic of human disc degeneration (fibrosis and ossification). Building on these exciting discoveries, we now aim to combine our unique IVD-"clockless" transgenic mouse, ex vivo IVD explant and clinical IVD samples to establish how circadian clock disruption leads to IVD degeneration and whether we can use pharmacological compounds that target clock genes, or other approaches (such as periodic heat pulses or osmotic mimetics) to entrain circadian rhythms in degenerative IVD and thereby promote tissue repair. This research holds strong potential to identify novel therapeutic strategies for low back pain, which will have a long lasting impact on the health and well-being of the ageing population. This is particularly important because demographic ageing and the modern 24/7 life style frequently disrupt our circadian rhythms which can significantly increase risk of many diseases, including low back pain.

Low back pain (LBP), caused by degeneration of the intervertebral disc (IVD), is amongst the most prevalent spinal diseases. It affects millions of individuals, causing severe pain and loss of mobility, with currently no long-term cure. Ageing is a major risk factor. However, we have limited understanding of why age increases susceptibility to disc degeneration and LBP. Our modern 24/7 society and ageing frequently disrupt circadian rhythms generated by our body clocks. We have discovered a functional clock in the IVD which weakens with age and its disruption in mice leads to tissue damage characteristic of human IVD degeneration. This project will establish mechanistic links between clock disruption and IVD tissue degeneration, and explore the therapeutic potential of targeting the body clock mechanisms (by clock-acting compounds, temperature cycles or osmolarity) to restore tissue function and promote repair.
Scientific Impact
This project will initially benefit a wide range of researchers (see Academic Beneficiaries). Establishing mechanistic links between IVD clock dysregulation and tissue damage will significantly advance our understanding of the rhythmic aspect of disc physiology and disease pathogenesis. Secondly, entrainment of circadian rhythms by temperature fluctuations and dynamic osmotic changes (associated with daily loading cycle) may also apply to other musculoskeletal tissues, and as such will impact on researchers in other fields of skeletal biology.
Novel Technology
To address the functional significance of the IVD clock, we have generated a unique conditional IVD-"clockless" mouse model. This is essential because current available models of circadian rhythm disruptions (e.g. whole body clock mutant mice, or mice kept under weekly reversal of light/dark cycle) lead to global disruptions to circadian rhythms, which will confound the interpretation of results. In addition, the use of clock gene reporter mice (PER2::Luciferase and VENUS::BMAL1) and human IVD clock reporter cell line models will greatly facilitate the accurate evaluation of the molecular circadian clocks.
Translational impact
Our project has revealed functional links between circadian clock mechanisms and IVD biology/degeneration. Drugs targeting clock genes (such as CRY1 and REV-ERBa) have already been proposed as potential therapeutics for human diseases, including diabetes and cancer. Our analysis strongly implicates these clock genes as regulators of key pathways in IVD function. Over the years, QJM has established collaborative links with pharmaceutical industries, which will ensure rapid translation of the research findings. In addition, our discoveries of new clock entrainment mechanisms through temperature or osmolarity could prompt completely new means of modulating circadian rhythms to alleviate symptoms of musculoskeletal diseases.
Societal and health impact
Our studies 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 great interest to the sufferers of low back pain, healthcare professionals, the general public and the elderly population. Our research will identify novel therapeutic strategies for spine diseases (including LBP), and may facilitate the design of "chronotherapy" or "circadian medicine" to improve the efficacy of current treatments and thus has enormous potential for improving health and quality of life. Furthermore, the quest for prognostic biomarkers also has to consider their potential daily variations. Our research may also reveal detrimental effects of rotating shift work to spine health and LBP, and therefore could influence policy-makers regarding how to best set up schedules for shift workers. Finally, understanding the time-of-day exacerbation of their symptoms may help LBP sufferers better manage their pain and mobility.