The Impact of Disrupting Sensory Innervation on Tibial Bone Mass

项目摘要 胫骨和腓骨骨折占每年骨折的10%，导致显著的发病率， 骨折后12个月内的死亡率为10%低骨矿物质密度可显著增加骨折 成骨细胞骨形成减少、成骨细胞骨吸收增加导致的风险 破骨细胞或两者。更深入地了解胫骨骨密度调节因素将有助于预防 通过识别高危个体和治疗胫骨骨密度低， 感觉神经与骨骼之间传递信号。两个信号传导方向都是骨稳态的关键方面， 骨骼健康感觉神经与骨的沟通与骨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通讯， 去神经支配与骨量减少有关。然而，目前还不清楚这些长期中断的影响 信号通路对骨骼健康的影响隐神经主要是感觉神经， 运动功能隐神经的损伤导致疼痛、麻木和神经本身的去神经支配。 初步研究表明，隐神经支配小鼠胫骨。初步数据 已经表明，隐神经的横断使胫神经纤维密度降低了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 矿物密度未知。我们假设隐神经去神经支配会改变骨重建 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和神经支配影响这些数据将决定 胫骨去神经支配将导致骨矿物质密度、微结构、细胞数量和 周转它还将进一步确定隐神经损伤后胫骨内神经支配丧失的区域。 为了描述骨感觉调节的机制，目标2将评估骨感觉调节的相对机制。 感觉神经纤维亚型对胫骨骨量的贡献，通过化学消融肽能和 非肽能感觉神经元，分别使用树脂毒素和IB 4-皂草素。由于CGRP已经 我们假设选择性消融肽能感觉纤维， 将导致骨丢失，而选择性消融非肽能感觉纤维不会改变骨 重塑或骨量。这些数据将揭示维持神经元功能所必需的感觉神经纤维亚型。 骨密度拟议的研究将确定隐神经作为一个重要的调节骨 胫骨内环境的稳定更深入地了解神经损伤对骨量的影响将有助于 阐明诱发个体胫骨骨折的新的危险因素。

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.