Role of Vitamin C in Low back Pain and Intervertebral Disc Degeneration

项目摘要/摘要 持续性背痛是全世界导致残疾的主要原因，也是最常见的原因之一。 替尼汀是处方阿片类药物，尽管它们改善功能的能力很差。慢性背痛威胁着 我们的经济健康，因为高卫生保健利用率和残疾人，以及我们的生活质量，由于 疼痛相关的痛苦，疼痛相关的阿片类药物滥用，抑郁和焦虑。40%的主要驱动力 在所有的腰痛(LBP)病例中，估计是由于椎间盘退变引起的疼痛。前- 症状治疗(如止痛药)或侵入性治疗(如脊椎注射、手术)有限 阿片类药物的疗效和风险分别与滥用阿片类药物或手术并发症有关。有一个 迫切需要安全有效的慢性LBP治疗方法，并可迅速应用于临床。 椎间盘退变与细胞外基质(ECM)成分的产生减少有关 包括胶原蛋白和蛋白多糖。DNA甲基化是一种表观遗传机制，调节基因 表达，并可根据当地、环境或药理因素进行修改。我们 以前已经表明，非侵入性治疗(跑步锻炼)可以减轻 慢性LBP，增加IVD胶原的产生，减少IVD的整体甲基化。抗坏血酸 (维生素C)对胶原蛋白的产生是必不可少的，并参与DNA甲基化的调节。 抗坏血酸日常摄入安全，其缺乏与肌肉骨骼疼痛有关。 老年人。虽然抗坏血酸在某些情况下具有止痛特性，并且对Colla- 关于基因合成和肌肉骨骼健康，其治疗LBP的潜力尚未被研究。 这项应用的总体目标是确定抗坏血酸治疗的疗效- 应用进行性IVD退变的临床前模型研究椎间盘源性LBP和IVD退变 与LBP相关的TION。我们的中心假设是抗坏血酸重新编程细胞外基质的表达 通过减少退行性IVD中的DNA甲基化，从而减弱导致椎间变性的LBP。在SPE中- 具体目标1，我们将检查长期补充抗坏血酸的疗效(4 几个月)使用小鼠模型来预防和治疗腰痛和腰椎间盘退变。具体而言 目的：研究维生素C对细胞外基质DNA甲基化及mRNA表达的影响。 基因，重点是胶原蛋白和蛋白多糖，并将这些数据与椎间盘病理相关联 以及LBP的行为迹象。预期结果是，我们将观察其治疗效果 抗坏血酸对LBP和IVD变性的影响(目标1)与IVD DNA甲基重编程相关 目标2)。这些结果将为使用非侵入性、安全、饮食 补充维生素C作为治疗椎弓根性腰椎病的方法。

PROJECT SUMMARY / ABSTRACT Persistent back pain is a leading cause of disability worldwide and one of the most common reasons pa- tients are prescribed opioids, despite their poor ability to improve function. Chronic back pain threatens our economic health due to high rates of health care utilization and disability and our quality of life due to pain-related suffering, pain-associated opioid misuse, depression, and anxiety. The primary driver in 40% of all low back pain (LBP) cases is estimated to be pain from intervertebral disc (IVD) degeneration. Ex- isting symptomatic (e.g., analgesics) or invasive (e.g., spinal injections, surgery) treatments have limited efficacy and are associated with risk for opioid misuse or surgical complications, respectively. There is an urgent need for safe and effective treatments for chronic LBP that can be rapidly translated to the clinic. Disc degeneration is associated with decreased production of extracellular matrix (ECM) components including collagen and proteoglycans. DNA methylation is an epigenetic mechanism that regulates gene expression and can be modified in response to local, environmental, or pharmacological factors. We have previously shown that a non-invasive treatment (running exercise) attenuates behavioral signs of chronic LBP, increases IVD collagen production, and decreases IVD global methylation. Ascorbic acid (vitamin C) is essential for collagen production and is involved in the regulation of DNA methylation. Ascorbic acid is safe for daily consumption and its deficiency is correlated with musculoskeletal pain in elderly. Although ascorbic acid exhibits analgesic properties in some conditions and is essential for colla- gen synthesis and musculoskeletal health, its therapeutic potential for LBP has not been studied. The overall objective for this application is to determine the therapeutic outcomes of ascorbic acid treat- ment in discogenic LBP and IVD degeneration using a pre-clinical model of progressive IVD degenera- tion associated with LBP. Our central hypothesis is that ascorbic acid reprograms expression of ECM genes by decreasing DNA methylation in degenerated IVDs, thereby attenuating discogenic LBP. In Spe- cific Aim 1, we will examine the therapeutic efficacy of long-term ascorbic acid supplementation (4 months) on the prevention and treatment of LBP and disc degeneration using a mouse model. In Specific Aim 2, we will determine the effects of vitamin C on DNA methylation and mRNA expression of ECM genes, with emphasis on collagens and proteoglycans, and will correlate these data to disc pathology and behavioral signs of LBP. The expected outcomes are that we will observe therapeutic effects of ascorbic acid on LBP and IVD degeneration (Aim 1) associated with reprogramming of IVD DNA methyl- ation (Aim 2). These results will provide critical proof-of-concept data for using noninvasive, safe, dietary vitamin C supplementation as a treatment for discogenic LBP.