Repurpose bone therapeutics for intervertebral disc degeneration in aged mice

项目摘要 腰椎间盘退变是腰痛的主要原因，而腰痛是导致工作的头号原因。 全世界80%的人一生中至少会受到一次残疾的影响。年纪较大的人容易患上 由于失去高度和水合作用而导致的椎间盘退行性变。疼痛会使椎间盘恶化 通过限制机动性和减少动态平衡所需的机械力而退化。因此， 有一种尚未得到满足的需求，即安全地保护老年人免受椎间盘退变的影响，在这里，我们 意欲改变现有骨疗法的用途，以减少/防止间盘丢失，从而恢复 老龄化人口的痛苦。椎间盘退变仍然是一个日益严重的问题，因为(1)美国 老年人口预计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。我们是 独一无二的定位，弥合了骨疗法对干细胞分子机制的知识缺口 腰椎间盘退变。腰椎间盘受压的老化和机械性损伤 会加剧细胞外基质的分解，但压迫比衰老更能刺激炎症。 相比之下，我们最近发现，缺失Wnt/β-catenin信号的抑制因子SOST，一种骨形成 合成代谢机制和遗传模拟方法注射抗硬化素抗体，增加了 椎间盘的结构特性和水化作用。另一种骨疗法显示出对 椎间盘是一种抗吸收的雷洛昔芬，一种非子宫靶向的雌激素激动剂，它也会增加 水与胶原蛋白的结合。在绝经后妇女中使用雷洛昔芬与缓解背痛有关 与未经治疗的女性相比，椎间盘高度更高。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，减少与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。 在这里，我们假设目前可用的治疗方法将刺激细胞外基质合成代谢和 预防幼年和老年小鼠受压所致的椎间盘退变。为了检验这一假设， 我们提出用老龄小鼠和分解代谢压迫作为椎间盘退变模型的两个目的。 在目标1中，我们将确定已知的激活Wnt信号的疗法是否可以防止IVD退化 通过对幼年和老年小鼠进行损伤性机械压缩。在目标2中，我们将确定雌激素是否 信号通过Wnt信号防止IVD退变，以及是否可以安全地通过 结合衰老小鼠的信号通路。这项提案将改变目前FDA批准的骨骼的用途 靶向途径持续受到变量椎间盘退变影响的预防药物 可能对老年人的腰椎间盘退行性变特别有益。

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.