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

下腰痛(LBP)是最常见的脊柱疾病之一，由脊柱内纤维软骨间盘退变引起。它影响着全世界数百万人，导致严重疼痛和行动不便，目前尚无长期治愈方法。老龄化是一个主要的风险因素。然而，我们并不完全理解为什么年龄会增加腰椎间盘退变和腰椎病的易感性。生物钟负责在行为和生理上产生24小时节律。衰老或倒班工作造成的节律紊乱会显著增加患病风险。至关重要的是，我们的团队第一次发现了腰间盘中的功能生物钟。这种外周生物钟随着年龄的增长而减弱，它的破坏导致了椎间盘退变的组织损伤特征。该项目将确定疾病的相关性，并探索该组织中生物钟的治疗潜力。具体地说，我们将使用我们的新型无时钟小鼠模型、椎间盘组织培养和患者样本来验证以下假设：1)。与休息/活动相关的每日负荷周期可重置IVD昼夜节律；扰乱IVD昼夜节律会损害组织的稳态/完整性，并导致对退变的易感性增加；靶向IVD时钟机制为椎间盘退变提供了一种新的治疗方法。我们的研究具有确定下腰痛的新治疗策略的强大潜力，因此在改善健康和生活质量方面具有巨大的潜力。此外，我们的研究结果强调，通过健康的生活方式保持健康的生物钟的重要性，这将对老龄化人口的健康和福祉产生长期的影响。这一点特别重要，因为人口老龄化和我们现代全天候社会日益增长的需求经常扰乱我们的生物钟，这可能会显着增加许多疾病的风险。

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.