Repurpose bone therapeutics for intervertebral disc degeneration in aged mice

重新利用骨疗法治疗老年小鼠椎间盘退变

• 批准号: 10709661
• 负责人: Nilsson Holguin
• 金额: $ 50.71万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-22 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10709661
• 关键词: Acute; Adult; Affect; Age; Aging; Agonist; Anabolism; Antibodies; Attenuated; Back Pain; Behavior; Behavioral Model; Binding; Biophysics; Bone structure; Cell Proliferation; Cells; Child; Collagen; Collection; Data; Dehydration; Dose; Early treatment; Economic Burden; Elderly; Ensure; Estrogen Receptor alpha; Estrogens; Etiology; Extracellular Matrix; FDA approved; Female; Generations; Genetic; Genetic Recombination; Glycine decarboxylase; Height; Histology; Homeostasis; Hydration status; Impairment; Individual; Inflammation; Injections; Intervertebral disc structure; Knowledge; LacZ Genes; Ligands; Low Back Pain; LoxP-flanked allele; Magnetic Resonance Imaging; Maintenance; Mechanics; Mediating; Metabolism; Modeling; Molecular; Mus; Natural regeneration; Occupations; Operative Surgical Procedures; Osteogenesis; Outcome; Ovariectomy; Pain; Palliative Care; Pathway interactions; Persons; Population; Positioning Attribute; Postmenopause; Prevention; Property; Proteoglycan; Raloxifene; Recording of previous events; Reporter; Signal Pathway; Signal Transduction; Statistical Data Interpretation; Strenuous Exercise; Structure; Substance P; Tail; Tamoxifen; Testing; Therapeutic; Time; Vertebral column; WNT Signaling Pathway; Water; Woman; age related; aged; aging population; analog; antagonist; beta catenin; bone; bone mass; chronic pain; disability; improved; inhibitor; intervertebral disk degeneration; male; mechanical force; men; nucleus pulposus; overexpression; pain behavior; palliative; pharmacologic; prevent; prophylactic; response; second harmonic; sex; socioeconomics; spinal disk injury; stem; transcription factor; transcriptome sequencing; young adult

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.

项目摘要 椎间盘退化是下腰痛的主要病因因素，这是作业的第一原因 全世界的残疾人在一生中至少影响80％的人。老年人容易 椎间盘变性通过椎间盘高度和水合的损失。疼痛会更糟椎间盘 通过限制迁移率并减少稳态所需的机械力来退化。所以， 没有必要的需要安全保护老年人免受椎间盘变性的侵害，在这里，我们 打算重新利用现有的骨治疗，以减少/预防椎间盘损失，从而返回 老龄化人口的疼痛。椎间盘变性仍然是一个日益增长的问题，因为（1）美国 老年人口预计是历史上第一次向外部人数儿童，（2）早期治疗 椎间盘退化保持姑息性和（3）激烈的社会经济伯恩。我们是 独特的位置以弥合骨治疗的分子机制中的知识差距 椎间盘变性。通过压缩，椎间盘的老化和机械损伤 细胞外基质的加剧分解，但压缩比衰老更刺激感染。 相比之下，我们最近发现Wnt/β-catenin信号传导的抑制剂的缺失，骨形成 合成代谢机制和抗骨蛋白抗体注射的遗传类似方法，增加了 椎间盘的结构特性和水合。另一种骨疗法显示出对 椎间盘是抗敏感性雷昔芬，一种非靶向雌激素激动剂，也会增加 水与胶原蛋白的结合。在绝经后妇女中使用雷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，雷昔芬增加 雄性和雌性小鼠的椎间盘高度减少了性别和年龄相关的椎间盘椎间盘变性 在雌性小鼠中，改善了旧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将刺激细胞外基质代谢和 防止年轻小鼠和老年小鼠压缩引起的椎间盘变性。为了检验这一假设， 我们提出了使用老年小鼠和分解代谢压缩作为椎间盘变性模型的两个目标。 在AIM 1中，我们将确定是否已知是否已知会激活Wnt信号传导会阻止IVD变性 通过年轻小鼠和老年小鼠的有害机械压缩。在AIM 2中，我们将确定雌激素是否 信号传导可防止通过Wnt信号传导IVD变性，以及是否可以安全地改善预防 结合老年小鼠的信号通路。该建议将复制当前FDA批准的骨头 靶向靶向途径始终受到椎间盘变性影响的预防疗法 条件，可能对椎间盘的椎间盘变性特别有益。