Endplate Sensory Innervations for LBP

LBP 的终板感觉神经支配

• 批准号: 10326802
• 负责人: Xu Cao
• 金额: $ 44.62万
• 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/10326802
• 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; Degenerative polyarthritis; Deterioration; Development; Dinoprostone; Disease; Elderly; Etiology; Evaluation; Exhibits; Frail Elderly; 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; Nature; Nerve; Nociceptors; Osteoclasts; PTK2 gene; Pain; Pathway interactions; Patients; Persistent pain; Persons; 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).

摘要 持续性疼痛，特别是在休息时，深刻地影响生活质量和日常身体活动，特别是在 老年人口。疼痛本身是未来功能衰退发展的危险因素。此外，委员会认为， 流动性的下降反过来又大大增加了许多慢性疾病的风险。下背痛（LBP） 这是一个非常常见的健康问题，影响大约80%的人在他们的生命过程中， 导致活动受限和缺勤的主要原因。因此，LBP的脊柱退行性变是最常见的 导致行动能力下降和身体虚弱的流行病。不幸的是，我们仍然不明白 LBP的来源，没有有效的疾病修饰疗法。 脊柱环关节被认为是一个功能单位，每个关节都对 机械载荷和老化退化。特别是，椎骨终板经历骨化， 在不平衡的机械力下或在老化过程中变得多孔。我们之前发现了大量 LBP患者和老年小鼠（脊柱超敏反应模型）中多孔软骨终板中的破骨细胞， 表明终板中有活跃的骨重建。我们还发现超过70%的破骨细胞 是衰老细胞，已报道其导致与年龄相关的组织功能障碍。此外，临床 啮齿类动物研究表明，多孔终板的神经密度高于正常终板 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LBP患者的一个重要因素。 患者LBP来源和小鼠脊髓超敏反应。我们最近发现破骨细胞分泌 轴突导向分子Netrin-1诱导感觉神经轴突在终板中生长。减少 破骨细胞抑制感觉神经支配终板。此外，我们已经证明，在 骨重建时，前列腺素E2（PGE 2）激活感觉神经上的EP 4受体， 交感神经紧张，诱导间充质基质细胞向成骨细胞分化。我们的试点数据 结果显示，在多孔终板中，衰老的破骨细胞、PGE 2和Netrin-1水平显著增加。 因此，我们处于一个独特的位置，以确定脊椎感觉神经失调的作用， 终板是脊柱功能单位随年龄退变的驱动因素。我们假设升高的PGE 2 衰老OC及其受体诱导的多孔EP中的浓度和感觉神经支配 过量Netrin-1分泌介导小鼠脊髓超敏反应（患者中的LBP）。具体地说， 我们将首先确定骨钙素SnCs对脊髓超敏反应的作用（目的1）。我们接下来将 探讨衰老破骨细胞产生的Netrin-1在多孔介质中的感觉神经支配机制 终板（目标2）。最后，我们将检查多孔终板中升高的PGE 2水平是否会诱导脊柱 脊柱退变期间的超敏反应（目的3）。