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事人员的一个主要健康问题，这一点现在已经得到证实。尽管从海湾战争和反恐战争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需要康复以恢复功能的常见损伤之一，而且之前的一项研究表明，海湾战争退伍军人在骨形成方面表现出缺陷。此外，PTSD还导致交感神经系统(SNS)的激活和下丘脑-垂体-肾上腺(HPA)轴的改变。HPA轴的变化可以通过调节皮质醇和生长激素(GH)来影响骨的形成，生长激素是骨的两个主要系统调节因子。就PTSD引起的HPA轴改变影响骨骼的分子途径而言，我们已经出于几个原因与IGF-I有关。首先，IGF-I在骨形成过程中至关重要，生长激素和皮质醇对骨的作用涉及IGF-I。其次，IGF-I参与了运动对骨骼合成代谢的影响，运动是骨形成的关键生理调节因素。第三，我们的初步数据显示，慢性应激抑制了体内IGF-I的表达和骨形成。基于这些理论基础，我们建议在本研究中检验以下假设：1)创伤后应激障碍影响峰值骨量的发育和骨质疏松的易感性；2)创伤后应激障碍对骨骼形成新骨的能力产生显著的负面影响；3)创伤后应激障碍对骨形成的影响部分是通过下调IGF-I的作用来实现的。为了测试PTSD引起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，我们将青春期前的小鼠置于单一的创伤应激下，并在4个月大时评估PTSD对峰值骨量和强度的影响，此时大多数骨骼已经形成。为了测试创伤后应激障碍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影响。胫骨轴向载荷模型将用于评估机械载荷对创伤后应激障碍和非创伤后应激障碍小鼠骨形成的合成代谢作用。接下来，我们将评估改善创伤后应激障碍症状的药物干预在挽救骨骼对机械应变的反应能力方面是否有效。为了验证创伤后应激障碍对骨骼的影响是通过减少IGF-I的作用来调节的假设，我们将检验机械负荷诱导的IGF系统成分表达水平的变化与骨形成标志物之间的相关性。为了确定IGF-I作用受损在介导创伤后应激障碍效应中的因果作用，我们将使用IGF-I作用增强的转基因小鼠模型来挽救骨骼上的创伤后应激障碍。对创伤后应激障碍影响骨形成过程的分子途径的了解将导致中和创伤后应激障碍效应的治疗方法，从而改善军人的骨骼健康。 公共卫生相关性： 项目简介创伤后应激障碍(PTSD)是战斗中最常见的精神障碍。由于创伤后应激障碍症状的复杂性和多变性，以及缺乏检测生化变化与创伤后应激障碍症状之间因果关系的实验研究，我们对创伤后应激障碍疾病过程的分子机制知之甚少。这项研究将利用最先进的技术在实验性动物模型中测试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。为确定创伤后应激障碍对骨骼影响的分子途径的拟议基础研究将导致未来有效治疗的发展，以最大限度地减少创伤后应激障碍对骨骼的负面影响，并改善退伍军人管理局和普通人群的总体幸福感。

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.