Repurpose bone therapeutics for intervertebral disc degeneration in aged mice

项目摘要 椎间盘退变是下背痛的主要病因，这是工作的头号原因。 全球80%的人在一生中至少有一次残疾。老年人容易出现 椎间盘高度和水合作用丧失导致椎间盘退变。疼痛会使椎间盘恶化 通过限制移动性和减少稳态所需的机械力来抑制退化。因此，我们认为， 安全地保护老年人免受椎间盘退变的需要尚未得到满足，在此，我们 旨在重新利用现有骨治疗剂以减少/防止椎间盘丢失并因此而返回 老年人的痛苦。椎间盘退变仍然是一个日益严重的问题，因为（1）美国 预计老年人口将在历史上首次超过儿童，（2）早期治疗 椎间盘退变仍然是姑息性的;（3）不断膨胀的社会经济负担。我们 独特的定位，以弥合知识差距的分子机制，骨治疗，以干 椎间盘退变椎间盘的老化和机械性损伤 加剧细胞外基质的分解，但压缩刺激炎症比老化更严重。 相比之下，我们最近发现，Wnt/β-Catenin信号抑制剂的缺失会导致骨形成， 合成代谢机制和抗sclerostin抗体注射的遗传类似物方法， 椎间盘的结构特性和水合作用。另一种骨治疗，显示出的好处， 雷洛昔芬是一种非子宫靶向雌激素激动剂， 水与胶原蛋白的结合。绝经后妇女使用雷洛昔芬可缓解背痛 和椎间盘高度高于未治疗的女性。我们的研究表明雷洛昔芬增加了 雄性和雌性小鼠的椎间盘高度，减少性别和年龄相关的椎间盘退变 在雌性小鼠中，改善老年小鼠疼痛相关行为的指标，并刺激Wnt和雌激素信号传导。 在这里，我们假设目前可用的治疗方法将刺激细胞外基质粘附， 预防年轻和老年小鼠压迫诱导的椎间盘退变。为了验证这个假设， 我们提出了两个目的，使用老年小鼠和分解代谢压迫作为椎间盘退变的模型。 在目标1中，我们将确定已知激活Wnt信号传导的疗法是否会预防IVD变性。 通过对年轻和老年小鼠的损伤性机械压迫。在目标2中，我们将确定雌激素是否 信号传导通过Wnt信号传导预防IVD变性，以及预防是否可以通过以下方式安全地改善： 结合老年小鼠的信号通路。这项提案将重新利用目前FDA批准的骨 靶向通路的药物持续受到可变椎间盘退变的影响， 条件，并可能特别有益于老年人的椎间盘退变。

Project Summary Intervertebral disc degeneration is a major etiological factor of low back pain, which is the #1 cause of job disability worldwide that affects 80% of people at least once in their lifetime. Older individuals are prone to intervertebral disc degeneration by a loss of disc height and hydration. Pain can worsen intervertebral disc degeneration by limiting mobility and reducing the mechanical forces necessary for homeostasis. Therefore, there is an unmet need to safely protect older individuals from intervertebral disc degeneration and, here, we intend to repurpose existing bone therapeutics to reduce/prevent intervertebral disc loss and consequently back pain in the aging population. Intervertebral disc degeneration remains a growing problem because (1) the US geriatric population is projected to outnumber children for the first time in history, (2) the early treatment of intervertebral disc degeneration remains palliative and (3) the ballooning socioeconomic burden. We are uniquely positioned to bridge the knowledge gap in the molecular mechanisms of bone therapeutics to stem intervertebral disc degeneration. Aging and mechanical injury of the intervertebral disc by compression both exacerbate breakdown of the extracellular matrix, but compression stimulates inflammation more so than aging. By contrast, we recently found that deletion of the inhibitor of Wnt/β-Catenin signaling sost, a bone formation anabolic mechanism and the genetic analog approach to anti-sclerostin antibody injection, increases the structural properties and hydration of the intervertebral disc. Another bone therapeutic that shows benefits to the intervertebral disc is anti-resorptive raloxifene, a non-uterine-targeting estrogen agonist, that also increases binding of water to collagen. Use of raloxifene in postmenopausal women is associated with relieving back pain and greater intervertebral disc height than non-treated women. Our studies show that raloxifene increases intervertebral disc height in male and female mice, reduces sex- and age-related intervertebral disc degeneration in female mice, improves metrics of pain-related behavior in old mice and stimulates Wnt and estrogen signaling. Here, we hypothesize that currently available therapeutics will stimulate extracellular matrix anabolism and prevent compression-induced intervertebral disc degeneration in young and aged mice. To test this hypothesis, we propose two aims using aged mice and catabolic compression as models of intervertebral disc degeneration. In aim 1, we will determine whether therapeutics known to activate Wnt signaling will prevent IVD degeneration by injurious mechanical compression in young and aged mice. In aim 2, we will determine whether estrogen signaling prevents IVD degeneration via Wnt signaling and whether prevention can be safely improved by combining the signaling pathways in aged mice. This proposal will repurpose current FDA-approved bone prophylactics that target pathways consistently impacted by intervertebral disc degeneration in variable conditions and may be specifically beneficial to intervertebral disc degeneration in the elderly.