The Impact of Disrupting Sensory Innervation on Tibial Bone Mass

项目总结 胫骨和腓骨骨折占每年骨质疏松性骨折的10%，导致严重的发病率 骨折后12个月内10%的死亡率。低骨密度会显著增加骨折的发生 成骨细胞骨形成减少，骨吸收增加的风险 破骨细胞或两者兼而有之。更多地了解调节胫骨骨密度的因素将有助于预防 通过识别高危个体和治疗胫骨低骨密度来治疗胫骨骨折。 感觉神经向骨骼发出信号，并从骨骼发出信号。这两个信号方向都是骨骼动态平衡的关键方面 骨骼健康。感觉神经与骨骼的联系与骨骼矿物质密度的增加有关 通过感觉神经与成骨细胞和破骨细胞之间的直接和间接联系，而 去神经与骨量减少有关。然而，目前尚不清楚这些活动的长期中断会产生什么影响 信号通路对骨骼健康有影响。隐神经主要是一种感觉神经， 运动功能。隐神经的损伤会导致神经本身的疼痛、麻木和失神经。 初步研究表明，隐神经支配小鼠的胫骨。初步数据 研究表明，切断隐神经可使胫神经纤维密度降低45%-60%。 胫骨近端最外侧的骨膜。然而，隐神经损伤对胫骨的影响 矿物质密度尚不清楚。我们假设去隐神经会改变骨重建。 在胫骨内导致骨量减少。为了检验这一假设，目标1将描述 隐神经切断对胫骨骨量及神经分布的影响。这些数据将决定是否 失去胫骨神经将导致骨密度、微结构、细胞数量和 营业额。它还将进一步确定隐神经损伤后胫骨内神经丢失的区域。 为了描绘骨骼感觉调节的机制，目标2将评估相对的 化学消融感觉神经纤维亚型对胫骨骨量的贡献 分别用树脂素和IB4-Saporin处理非肽能感觉神经元。正如CGRP一直以来 证明促进骨合成代谢，我们假设选择性消融肽能感觉神经纤维 会导致骨丢失，而选择性消融非肽能感觉神经纤维不会改变骨 重塑或骨量。这些数据将揭示维持健康所必需的感觉神经纤维亚型 骨矿密度。拟议中的研究将把隐神经定义为骨骼的重要调节器。 胫骨的动态平衡。更好地了解神经损伤对骨量的影响将有助于 阐明易患胫骨骨折的新危险因素。

PROJECT SUMMARY Tibia and fibula fractures account for 10% of annual osteoporotic fractures leading to significant morbidity with a 10% mortality rate within 12 months of fracture. Low bone mineral density can dramatically increase fracture risk resulting from a decrease in bone formation by the osteoblast, an increase in bone resorption by the osteoclast, or both. A greater understanding of factors regulating tibial bone mineral density will help prevent tibial fracture through identification of at-risk individuals and treatment of low tibial bone mineral density. Sensory nerves signal to and from bone. Both signaling directions are critical aspects of bone homeostasis and bone health. Sensory nerve communication with bone has been linked to an increase in bone mineral density through direct and indirect communication between sensory nerves and both osteoblast and osteoclasts while denervation is linked to reduced bone mass. However, it is unclear what impact long-term disruption of these signaling pathways has on bone health. The saphenous nerve is primarily a sensory nerve with no known motor function. Injury to the saphenous nerve results in pain, numbness, and denervation of the nerve itself. Preliminary studies have demonstrated that the saphenous nerve innervates the tibia in mice. Preliminary data has shown that transection of the saphenous nerve reduces tibial nerve fiber density by 45-60% in the proximal, lateral-most periosteum of the tibia. However, the impact of saphenous nerve injury on tibial bone mineral density is unknown. We hypothesize that saphenous nerve denervation will alter bone remodeling within the tibia resulting in reduced bone mass. In order to test this hypothesis, Aim 1 will characterize the impact of saphenous nerve transection on tibial bone mass and innervation. These data will determine whether denervation of the tibia will result in a decreased bone mineral density, microarchitecture, cell number, and turnover. It will also further identify regions of innervation loss within the tibia following saphenous nerve injury. In an effort to delineate the mechanism of sensory regulation of bone, Aim 2 will assess the relative contribution of sensory nerve fiber subtypes on tibial bone mass through chemical ablation of peptidergic and non-peptidergic sensory neurons using resiniferatoxin and IB4-Saporin, respectively. As CGRP has been demonstrated to promote bone anabolism, we hypothesize that selective ablation of peptidergic sensory fibers will result in bone loss whereas selective ablation of non-peptidergic sensory fibers will not alter bone remodeling or bone mass. These data will reveal the sensory nerve fiber subtype necessary for maintaining bone mineral density. The proposed studies will define the saphenous nerve as an important regulator of bone homeostasis in the tibia. A greater understanding of the impact of nerve injury on bone mass will aid in elucidating new risk factors predisposing individuals to tibial fracture.