Impact of PTSD on Bone Formation

描述（由申请人提供）： 摘要创伤后应激障碍是军人的一个主要健康问题。尽管从海湾战争和反恐战争中归来的退伍军人中有一部分抱怨骨痛，但人们对创伤后应激障碍对骨骼系统的影响一无所知。在这项研究中，我们的重点是创伤后应激障碍对骨形成的影响，因为骨骼损伤是军事人员中常见的损伤之一，需要康复恢复功能，因为以前的研究表明，海湾战争退伍军人表现出骨形成的缺陷。此外，PTSD导致交感神经系统（SNS）激活和下丘脑-垂体-肾上腺（HPA）轴的改变已被证实。HPA轴的改变可以通过调节皮质醇和生长激素（GH）这两种主要的骨系统调节因子来影响骨形成。PTSD诱导的HPA轴变化可能影响骨的分子途径方面，我们有几个原因涉及IGF-I。首先，IGF-I在骨形成过程中至关重要，GH和皮质醇对骨的作用涉及IGF-I。其次，IGF-I参与调节运动对骨骼合成代谢的影响，这是骨形成的关键生理调节剂。第三，我们的初步数据表明，慢性应激抑制体内IGF-I表达和骨形成。基于这些基本原理，我们建议在本研究中验证以下假设：1）PTSD影响峰值骨量的发展和骨质疏松症的易感性; 2）PTSD对骨骼响应机械应变构建新骨的能力产生显著的负面影响; 3）PTSD对骨形成的影响部分通过下调IGF-I作用来介导。为了测试PTSD诱导的神经内分泌激素的变化是否会对峰值骨量的获得产生负面影响，我们将使青春期前小鼠经历单一创伤应激，并评估PTSD对4个月龄时大部分骨已经形成的峰值骨量和强度的后果.为了测试PTSD是否对机械负荷诱导的骨形成产生负面影响，我们将评估创伤应激对机械负荷诱导的小鼠成骨细胞数量和活性增加的后果。胫骨轴向负荷模型将用于评价机械负荷对PTSD和非PTSD小鼠骨形成的合成代谢作用。接下来，我们将评估改善PTSD症状的药物干预是否能有效挽救骨骼对机械应变的反应能力。为了验证PTSD对骨的影响是通过降低IGF-I作用介导的这一假设，我们将研究机械负荷诱导的IGF系统组分表达水平变化与骨形成标志物之间的相关性。为了确定IGF-I作用受损在介导PTSD效应中的因果作用，我们将使用IGF-I作用增加的转基因小鼠模型来挽救PTSD对骨骼的影响。了解创伤后应激障碍影响骨形成过程的分子途径将导致治疗方法，以中和创伤后应激障碍的影响，从而改善军人的骨骼健康。 公共卫生相关性： 创伤后应激障碍（PTSD）是由战斗引起的最普遍的精神障碍。由于PTSD症状的复杂性和多变性，以及缺乏测试生化变化和PTSD症状之间因果关系的实验研究，我们对PTSD疾病过程的分子机制知之甚少。本研究将使用最先进的技术在实验动物模型中测试PTSD如何影响骨形成过程以及胰岛素样生长因子调节系统是否参与介导PTSD对骨形成过程的影响。拟议的基础研究，以确定创伤后应激障碍对骨骼影响的分子途径，将导致未来开发有效的治疗方法，以尽量减少创伤后应激障碍对骨骼的负面影响，并改善VA和一般人群的总体健康状况。

DESCRIPTION (provided by applicant): Abstract It is now well established that PTSD is a major health issue in military personnel. Although a proportion of returning veterans from the Gulf war and war on terrorism complain of bone aches, nothing is known about the impact of PTSD on the skeletal system. In this study, our focus is on PTSD effects on bone formation since skeletal injury is one of the common injuries among military personnel that require rehabilitation for restoration of function and since a previous study demonstrated that Gulf war veterans exhibit a deficiency in bone formation. Furthermore, it is well established that PTSD leads to the activation of sympathetic nervous system (SNS) and changes in hypothalamus-pituitary-adrenal (HPA) axis. The changes in HPA axis can influence bone formation by regulating cortisol as well as growth hormone (GH), two major systemic regulators of bone. In terms of the molecular pathway by which PTSD-induced changes in HPA axis could influence bone, we have implicated IGF-I for several reasons. First, IGF-I is critically important in bone formation process and the actions of GH and cortisol on bone involve IGF-I. Second, IGF-I is involved in mediating the skeletal anabolic effects of exercise, a key physiological regulator of bone formation. Third, our preliminary data show that chronic stress inhibits IGF-I expression and bone formation in vivo. Based on these rationale, we propose to test the following hypotheses in this study: 1) PTSD influences development of peak bone mass and susceptibility to osteoporosis; 2) PTSD exerts significant negative impact on the ability of skeleton to build new bone in response to mechanical strain; and 3) PTSD effect on bone formation is mediated in part via down-regulation of IGF-I action. To test if PTSD- induced changes in neuroendocrine hormones will have a negative impact on acquisition of peak bone mass, we will subject prepubertal mice to a single traumatic stress and evaluate the consequence of PTSD on peak bone mass and strength at 4 months of age when majority of bone has formed. To test if PTSD exerts negative effects on mechanical loading-induced bone formation, we will evaluate the consequence of traumatic stress on mechanical loading-induced increase in the number and activity of osteoblasts in mice. Tibial axial loading model will be used to evaluate the anabolic effects of mechanical loading on bone formation in PTSD and non-PTSD mice. We will next evaluate if pharmacological intervention to ameliorate PTSD symptoms is effective in rescuing the ability of skeleton to respond to mechanical strain. To test the hypothesis that PTSD effects on bone are mediated via decreased IGF-I action, we will examine the correlation between changes in mechanical loading-induced expression levels of IGF system components and bone formation markers. To establish a causal role for impaired IGF-I action in mediating PTSD effects, we will use a transgenic mouse model with increased IGF-I action to rescue PTSD effects on the skeleton. An understanding of the molecular pathway by which PTSD influences bone formation process will lead to therapeutic approaches to neutralize PTSD effect and thereby improve skeletal health in military personnel. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Post traumatic stress disorder (PTSD) is the most prevalent mental disorder arising from combat. We know very little on the molecular mechanisms of the PTSD disease process because of the complexity and variability of PTSD symptoms and lack of experimental studies testing the cause and effect relationship between biochemical changes and PTSD symptoms. This study will test how PTSD influences bone formation process and whether insulin-like growth factor regulatory system is involved in mediating PTSD effects on bone formation process in an experimental animal model using state-of-the art techniques. The proposed basic research to identify the molecular pathways for PTSD effects on bone will lead to the future development of effective therapies to minimize the negative effects of PTSD on bone and improve the general well-being in the VA and in the general population.