Endplate Sensory Innervations for LBP

摘要 持续性疼痛，特别是在休息时，会深刻影响生活质量和日常体力活动，尤其是在 老年人口。疼痛本身是未来功能衰退发展的危险因素。此外， 行动能力下降反过来又会显著增加患许多慢性病的风险。下腰痛(LBP)是 一种极其常见的健康问题，影响大约80%的人的一生，是 活动受限和缺勤的主要原因。因此，腰椎退行性变是最常见的 导致行动不便和虚弱的流行疾病。不幸的是，我们仍然不理解 LBP是LBP的来源，目前还没有有效的疾病修饰疗法。 脊柱双关节被认为是一个功能单位，每个关节对 机械载荷随老化而退化。特别是，椎体终板会发生骨化和 在不平衡的机械力或老化过程中变得疏松。我们之前发现了大量的 LBP患者和老年小鼠(脊髓超敏模型)多孔性硬化终板中破骨细胞的变化 提示终板有活跃的骨质重塑。我们还发现超过70%的破骨细胞 是衰老细胞，据报道会导致衰老相关的组织功能障碍。此外，临床上 啮齿动物研究表明，多孔性终板的神经密度高于正常终板。 终板在LBP患者和动物模型中的表达，表明异常支配的终板可能是一种 患者的LBP来源和小鼠的脊髓过敏。我们最近发现破骨细胞可以分泌 Netrin-1，轴突引导分子，诱导终板内感觉神经轴突生长。减少 破骨细胞抑制感觉神经向终板的支配。此外，我们已经证明，在 骨重塑，前列腺素E2(PGE2)激活其感觉神经上的EP4受体减少 交感神经张力，诱导间充质基质细胞向成骨细胞分化。我们的试点数据 显示衰老的破骨细胞，PGE2和Netrin-1在多孔性终板中的水平显著升高。 因此，我们处于一个独特的位置来确定脊椎感觉神经失调的作用。 终板作为脊髓功能单位退行性变的驱动力，随着年龄的增长。我们假设前列腺素E_2升高 衰老OCS诱导的多孔性EP的浓度和感觉神经支配 过量分泌Netrin-1介导了小鼠的脊髓超敏反应(患者为LBP)。具体来说， 我们将首先确定破骨细胞对脊柱超敏反应的影响(目标1)。接下来，我们将 多孔性衰老破骨细胞产生的Netrin-1感觉神经支配机制的研究 端板(目标2)。我们将最终检查多孔终板中升高的PGE2水平是否会导致脊髓 脊柱退行性变中的过敏症(目标3)。

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).