Endplate Sensory Innervations for LBP

LBP 的终板感觉神经支配

• 批准号: 10090196
• 负责人: Xu Cao
• 金额: $ 46.72万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-15 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10090196
• 关键词: Affect; Afferent Neurons; Age; Aging; Analgesics; Animal Model; Animals; Arachidonic Acids; Attenuated; Avil; Axon; Blood Vessels; Bone remodeling; Cell Aging; Cells; Characteristics; Chronic; Chronic Disease; Clinical; Clinical Research; Consensus; Data; Deterioration; Development; Dinoprostone; Disease; Elderly; Etiology; Evaluation; Exhibits; Functional disorder; Future; Health; Histologic; Hypersensitivity; Intervertebral disc structure; Joints; Lead; Life; Life Cycle Stages; Longevity; Low Back Pain; Magnetic Resonance Imaging; Mechanics; Mediating; Modeling; Mus; NTN1 gene; Nerve; Nociceptors; Osteoclasts; PTK2 gene; Pain; Pathway interactions; Patients; Persistent pain; Physical activity; Physiologic Ossification; Population; Porosity; Positioning Attribute; Quality of life; Reporting; Rest; Risk; Risk Factors; Rodent; Role; Sensory; Signal Transduction; Skeleton; Source; Spinal; Symptoms; Tissues; Vertebral column; Work; Zoledronic Acid; afferent nerve; aged; axon growth; axon guidance; base; behavior test; bisphosphonate; cost; cyclooxygenase 2; density; driving force; experimental study; frailty; functional decline; improved; joint destruction; mechanical force; mechanical load; medical attention; mesenchymal stromal cell; microCT; mouse model; nerve supply; osteoblast differentiation; pain patient; receptor; response; senescence; sensory mechanism; skeletal; spine bone structure; subchondral bone; systematic review; tomography

ABSTRACT Persistent pain, particularly at rest, profoundly affects quality of life and daily physical activity, especially in the elderly population. Pain itself is a risk factor for the development of future functional decline. Moreover, decrease in mobility in turn significantly increases the risk of many chronic diseases. Low back pain (LBP) is an extremely common health problem and affects roughly 80% of people during their life course and is the leading cause of activity limitation and work absence. Thus, spinal degeneration with LBP is one of the most prevalent diseases leading to a decline in mobility and frailty. Unfortunately, we still do not understand the source of LBP and there is no effective disease-modified therapy. Spinal amphiarthrodial joints are recognized as a functional unit, each of which exhibit unique responses to mechanical loading and degenerate with aging. Especially, vertebral endplates undergo ossification and become porous under unbalance mechanical forces or during aging. We have previously found a large number of osteoclasts in the porous sclerotic endplates in LBP patients and aged mice (spinal hypersensitivity model), suggesting active bone remodeling in endplates. We have also identified that over 70% of these osteoclasts are senescent cells, which have been reported to lead to age associated tissue dysfunction. Moreover, clinical and rodent animal studies demonstrated that nerve density was higher in porous endplates than that in normal endplates in LBP patients and animal models, suggesting that the aberrantly innervated endplates may be a source of LBP in patients and spinal hypersensitivity in mice. We have recently shown that osteoclasts secrete Netrin-1, an axonal guidance molecule, to induce sensory nerve axonal growth in the endplates. Reduction of osteoclasts inhibited the sensory innervation into endplates. Furthermore, we have demonstrated that during bone remodeling, prostaglandin E2 (PGE2) activates its EP4 receptor on sensory nerves to decrease sympathetic tone, which induced osteoblastic differentiation of mesenchymal stromal cells. Our pilot data showed senescent osteoclasts, PGE2 and Netrin-1 levels were significantly increased in porous endplates. Therefore, we are in a unique position to determine the role of sensory nerve dysregulation of the vertebral endplate as the driver of spinal functional unit degeneration with aging. We hypothesize that elevated PGE2 concentrations and sensory innervation in the porous EP induced by senescent OCs and their secretion of excessive Netrin-1 mediate spinal hypersensitivity in mice (LBP in patients). Specifically, we will first determine the effect of osteoclastic SnCs on spinal hypersensitivity (Aim 1). We will next investigate the mechanism of sensory innervation by senescent osteoclast-produced Netrin-1 in porous endplates (Aim 2). We will finally examine if the elevated PGE2 level in porous endplates induce spinal hypersensitivity during spine degeneration (Aim 3).

抽象的 持续性疼痛，尤其是休息时的疼痛，会严重影响生活质量和日常身体活动，尤其是在休息时。 老年人口。疼痛本身就是未来功能衰退的一个风险因素。而且， 活动能力下降反过来又显着增加了许多慢性疾病的风险。腰痛 (LBP) 是 一个极其常见的健康问题，影响着大约 80% 的人的一生，是 活动受限和缺勤的主要原因。因此，LBP 引起的脊柱退变是最常见的退行性疾病之一。 流行疾病导致活动能力下降和虚弱。不幸的是，我们仍然不明白 LBP 的来源，并且没有有效的疾病改良疗法。 脊柱双关节被认为是一个功能单位，每个关节都表现出独特的反应 机械负荷并随着老化而退化。特别是，椎骨终板会发生骨化， 在不平衡机械力或老化过程中变得多孔。之前我们已经发现了大量的 LBP 患者和老年小鼠多孔硬化终板中的破骨细胞（脊柱过敏模型）， 表明终板中的主动骨重塑。我们还发现，超过 70% 的破骨细胞 是衰老细胞，据报道它们会导致与年龄相关的组织功能障碍。此外，临床 和啮齿动物研究表明，多孔终板的神经密度高于正常的神经密度 LBP 患者和动物模型中的终板，表明异常神经支配的终板可能是 患者腰痛的来源和小鼠脊髓超敏反应。我们最近发现破骨细胞分泌 Netrin-1 是一种轴突引导分子，可诱导终板中的感觉神经轴突生长。减少 破骨细胞抑制终板的感觉神经支配。此外，我们还证明了在 骨重塑，前列腺素E2（PGE2）激活感觉神经上的EP4受体以减少 交感神经张力，诱导间充质基质细胞的成骨细胞分化。我们的试点数据 显示衰老的破骨细胞、多孔终板中的 PGE2 和 Netrin-1 水平显着增加。 因此，我们处于独特的地位来确定椎体感觉神经失调的作用 终板作为脊柱功能单位随衰老退化的驱动因素。我们假设 PGE2 升高 衰老 OC 及其诱导的多孔 EP 中的浓度和感觉神经支配 过量的 Netrin-1 分泌会介导小鼠脊髓过敏（患者 LBP）。具体来说， 我们将首先确定破骨细胞 SnCs 对脊柱过敏的影响（目标 1）。我们接下来 研究多孔中衰老破骨细胞产生的 Netrin-1 的感觉神经支配机制 端板（目标 2）。我们最终将检查多孔终板中 PGE2 水平升高是否会诱发脊髓损伤 脊柱退化期间的过敏（目标 3）。