Targeting circadian clock mechanisms in the intervertebral disc towards therapies for low back pain

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Low back pain (LBP), caused by degeneration of the fibro-cartilaginous 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 rhythms in behaviour and physiology. Rhythm disruptions by ageing or shift work can significantly increase disease risks. Crucially, our group, for the first time, has 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. This project will establish the disease relevance and explore the therapeutic potential of the body clocks in this tissue. Specifically, we will use our novel disc "clockless" mouse model, intervertebral disc explant culture and patient samples to test the following hypotheses: 1). Daily loading cycle associated with rest/activity can reset the IVD circadian rhythm; 2). Disruption to the IVD circadian rhythm compromises tissue homeostasis/integrity, and leads to increased susceptibility to degeneration; 3). Targeting IVD clock mechanisms provide a novel therapeutic approach for disc degeneration. Our research holds strong potential to identify novel 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.