Mechanisms of Systemic Bone Loss Following Femur Fracture in Mice

项目概要/摘要： 每年有200万人骨折，造成190亿美元的医疗费用， 骨质疏松症是一种“无症状疾病”，在骨折前通常没有明显的症状， 很难诊断未来骨折的风险。有趣的是，未来骨折风险的最佳预测因素是 任何骨骼部位的既往骨折史，即使在控制骨矿物质密度后。的病因 这种关系尚不清楚，但骨折可能会引起全身性骨吸收反应， 某些情况会主动地和永久地损害整个骨骼。然而，全身骨质流失 骨折后的骨丢失还没有完全特征化，并且这种骨丢失的具体机制 未被确认。我们实验室的初步数据表明，骨折会主动减少骨小梁 在小鼠损伤后两周内远端骨骼部位的体积。然而，重大的知识差距 仍然关注影响骨折后骨丢失和恢复的因素， 这些机制有助于这种适应性反应。确定这些因素是实现以下目标的关键一步： 确定治疗靶点和治疗的机会窗口。在拟议的研究中，我们将 确定基于年龄和性别的差异、剂量依赖性（基于损伤严重程度）和特异性 小鼠骨折后全身性骨丢失的机制，包括损伤诱导的炎症和 骨细胞的骨重建我们假设：1）雄性和雌性小鼠将表现出不同的 骨折后全身性骨丢失的程度，2）老年人从这种骨丢失中恢复将减少， 小鼠，3）全身性骨丢失的程度将通过损伤的严重程度来预测，4）抑制骨丢失的程度， 炎性细胞因子白细胞介素6（IL-6）将减少全身性骨丢失反应，和5）骨细胞- 缺陷小鼠将表现出降低的骨吸收反应。在目标1中，我们将确定基于年龄和性别的 小鼠股骨骨折后全身骨丢失和恢复的差异。在目标2中，我们将确定 基于损伤严重程度的全身性骨丢失的剂量依赖性，以及损伤诱导的骨丢失的贡献。 炎症，特别是IL-6。在目标3中，我们将确定骨细胞对全身骨的贡献 使用骨细胞功能障碍的遗传小鼠模型（Bcl-2转基因小鼠）的反应丧失。这些研究 将研究新的假设，即骨折主动减少骨量系统，从而 增加了将来所有骨骼部位骨折的风险。这些研究将扩大我们对 急性损伤的全身效应，并可能导致旨在保护长期 骨质疏松症患者的骨骼健康。

Project Summary/Abstract: Two million broken bones accounting for $19 billion dollars in medical costs occur each year because of the “silent disease” of osteoporosis, which often progresses with no noticeable symptoms prior to fracture, and is difficult to diagnose with respect to future fracture risk. Interestingly, the best predictor of future fracture risk is a previous history of fracture at any skeletal site, even after controlling for bone mineral density. The etiology of this relationship is unknown, but it is likely that fracture causes a systemic bone resorption response that under certain conditions can actively and permanently compromise the entire skeleton. However, systemic bone loss following fracture has not been thoroughly characterized, and the specific mechanisms of this bone loss have not been identified. Preliminary data from our lab show that bone fracture actively decreases trabecular bone volume at distant skeletal sites within two weeks post-injury in mice. However, significant knowledge gaps remain concerning factors that affect the loss and recovery of bone following fracture, and identification of mechanisms contributing to this adaptive response. Identification of these factors is a crucial step toward identifying therapeutic targets and the window of opportunity for treatment. In the proposed studies we will determine age- and sex-based differences, dose-dependence (based on injury severity), and specific mechanisms of systemic bone loss following fracture in mice, including injury-induced inflammation and osteocytic perilacunar remodeling. We hypothesize that: 1) male and female mice will exhibit different magnitudes of systemic bone loss following fracture, 2) recovery from this bone loss will be diminished in older mice, 3) the magnitude of systemic bone loss will be predicted by the severity of injury, 4) inhibition of the inflammatory cytokine interleukin 6 (IL-6) will reduce the systemic bone loss response, and 5) osteocyte- deficient mice will exhibit a reduced bone resorption response. In Aim 1 we will determine age- and sex-based differences in systemic bone loss and recovery following femur fracture in mice. In Aim 2 we will determine the dose-dependence of systemic bone loss based on injury severity, and the contribution of injury-induced inflammation, in particular IL-6. In Aim 3 we will determine the contribution of osteocytes to the systemic bone loss response using a genetic mouse model of osteocyte dysfunction (Bcl-2 transgenic mice). These studies will investigate the novel hypothesis that bone fracture actively decreases bone mass systemically, thereby increasing the risk of future fractures at all skeletal sites. These studies will expand our understanding of the systemic effects of an acute injury, and may lead to therapeutic strategies aimed at preserving the long-term skeletal health of osteoporotic patients.