Impact of PTSD on Bone Formation

PTSD 对骨形成的影响

• 批准号: 7750631
• 负责人: SUBBURAMAN MOHAN
• 金额: --
• 依托单位: VA LOMA LINDA HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7750631
• 关键词: Ache; Adrenal Cortex Hormones; Adverse effects; Age; Age-Months; Animals; Area; Attenuated; Basic Science; Behavioral; Biochemical; Biological; Biological Process; Brain; Cessation of life; Chronic; Chronic stress; Clonidine; Communication; Control Groups; Corticotropin; Data; Defect; Development; Disease; Down-Regulation; Drug usage; Dual-Energy X-Ray Absorptiometry; Event; Exercise; Exhibits; Experimental Animal Model; Experimental Models; Exposure to; Fatigue; Fluoxetine; Fracture; Freedom; Fright; Future; General Population; Glucocorticoids; Goals; Growth Factor; Gulf War; Headache; Healed; Health; Hormones; Human; Hydrocortisone; Hypothalamic structure; Individual; Inflammatory; Injury; Insulin-Like Growth Factor I; Insulin-Like Growth-Factor-Binding Proteins; Intervention; Label; Lead; Left; Life; Link; Major Depressive Disorder; Measurement; Measures; Mechanics; Mediating; Mediator of activation protein; Mental Depression; Mental Health; Mental disorders; Metals; Military Personnel; Modeling; Molecular; Monitor; Mus; Musculoskeletal; Natural Disasters; Neurosecretory Systems; Osteoblasts; Osteogenesis; Osteoporosis; Pathway interactions; Patients; Personal Satisfaction; Physical therapy; Physiological; Pituitary-Adrenal System; Post-Traumatic Stress Disorders; Predisposition; Prevalence; Prevalence Study; Procedures; Process; Proteins; Psychological Factors; Public Health; Publishing; RNA; Rattus; Recovery; Rehabilitation therapy; Reporting; Research; Reverse Transcriptase Polymerase Chain Reaction; Right-On; Risk; Rodent; Role; Serum; Services; Shock; Skeletal system; Skeleton; Soldier; Somatomedins; Somatotropin; Stimulus; Stress; Structure; Sympathetic Nervous System; Symptoms; System; Techniques; Telephone; Terrorism; Testing; Tetracyclines; Therapeutic; Time; Torsion; Transgenic Mice; United States; Veterans; War; Woman; abstracting; attenuation; authority; base; behavior test; bone; bone healing; bone loss; bone mass; bone metabolism; bone strength; chronic depression; combat; cytokine; effective therapy; foot; healing; improved; in vivo; member; men; mouse model; neuropeptide Y; operation; osteoporosis with pathological fracture; prepuberty; programs; public health relevance; receptor; repaired; research study; response; restoration; skeletal; skeletal injury; stressor; substantia spongiosa; tibia

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.

描述（由申请人提供）： 摘要 众所周知，创伤后应激障碍（PTSD）是军人的一个主要健康问题。尽管一部分从海湾战争和反恐战争归来的退伍军人抱怨骨痛，但人们对创伤后应激障碍（PTSD）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（PTSD）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，需要康复以恢复功能，而且之前的一项研究表明，海湾战争退伍军人表现出骨形成缺陷。此外，众所周知，PTSD 会导致交感神经系统 (SNS) 的激活和下丘脑-垂体-肾上腺 (HPA) 轴的变化。 HPA 轴的变化可以通过调节皮质醇和生长激素 (GH) 这两种主要的骨骼系统调节剂来影响骨形成。就 PTSD 诱导的 HPA 轴变化影响骨骼的分子途径而言，我们出于多种原因将 IGF-I 纳入其中。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都涉及IGF-I。其次，IGF-I 参与调节运动的骨骼合成代谢作用，是骨形成的关键生理调节剂。第三，我们的初步数据表明，慢性应激会抑制体内 IGF-I 的表达和骨形成。基于这些基本原理，我们建议在本研究中检验以下假设：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而构建新骨的能力产生显着的负面影响； 3) PTSD 对骨形成的影响部分是通过 IGF-I 作用的下调介导的。为了测试 PTSD 诱导的神经内分泌激素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创伤应激下，并评估 PTSD 对 4 个月龄时峰值骨量和强度的影响。大部分骨头已经形成。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影响。胫骨轴向载荷模型将用于评估机械载荷对 PTSD 和非 PTSD 小鼠骨形成的合成代谢影响。接下来我们将评估改善 PTSD 症状的药物干预是否能有效恢复骨骼对机械应变的反应能力。为了检验 PTSD 对骨骼的影响是通过 IGF-I 作用减少介导的假设，我们将检查机械负荷诱导的 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 PTSD 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 PTSD 对骨骼的影响。了解 PTSD 影响骨形成过程的分子途径将有助于找到中和 PTSD 效应的治疗方法，从而改善军事人员的骨骼健康。 公共卫生相关性： 项目叙述 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，并且缺乏测试生化变化与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。拟议的基础研究旨在确定 PTSD 对骨骼影响的分子途径，这将有助于未来有效疗法的开发，以最大限度地减少 PTSD 对骨骼的负面影响，并改善 VA 和普通人群的总体健康状况。