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

项目总结/摘要 持续性背痛是全球残疾的主要原因，也是最常见的原因之一。 尽管病人改善功能的能力很差，但他们还是被开了阿片类药物。慢性背痛威胁 我们的经济健康是由于高比例的医疗保健利用率和残疾，我们的生活质量是由于 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 据估计，所有腰痛（LBP）病例中的70%是椎间盘（IVD）退变引起的疼痛。前 无症状（例如，镇痛剂）或侵入性（例如，脊椎注射、手术）治疗有限 有效性，并分别与阿片类药物滥用或手术并发症的风险相关。有一个 迫切需要安全有效的治疗慢性LBP，可以迅速转化为临床。 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聚糖。DNA甲基化是一种表观遗传机制， 表达，并且可以响应于局部、环境或药理学因素而被修饰。我们 先前已经表明，非侵入性治疗（跑步锻炼）减弱了 慢性LBP，增加IVD胶原蛋白产生，并降低IVD整体甲基化。抗坏血酸 （维生素C）是胶原蛋白产生所必需的，并参与DNA甲基化的调节。 抗坏血酸是安全的日常消费和它的不足是与肌肉骨骼疼痛， 老人虽然抗坏血酸在某些情况下具有镇痛作用，并且是胶原蛋白所必需的， 基因合成和肌肉骨骼健康，其治疗LBP的潜力尚未研究。 本申请的总体目标是确定抗坏血酸治疗的治疗结果， 使用进行性IVD退行性变的临床前模型观察椎间盘源性LBP和IVD退行性变 与LBP相关的问题我们的中心假设是，抗坏血酸重编程ECM的表达， 通过降低退行性IVD中的DNA甲基化，从而减弱椎间盘源性LBP。在特殊情况下， cific目的1，我们将检查长期补充抗坏血酸的治疗效果（4 月）对LBP和椎间盘退变的预防和治疗。在特定 目的2：探讨维生素C对细胞外基质DNA甲基化和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学相关联 和LBP的行为迹象。预期结果是，我们将观察 抗坏血酸对LBP和IVD变性（Aim 1）的影响，与IVD DNA甲基化重编程相关。 （目标2）。这些结果将为使用非侵入性，安全，饮食 维生素C补充剂作为椎间盘源性LBP的治疗。

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.