Impact of PTSD on Bone Formation

摘要 现在已经确定创伤后应激障碍是军事人员的主要健康问题。 尽管一部分从海湾战争和反恐战争中返回的退伍军人抱怨说， 虽然创伤后应激障碍会导致骨骼疼痛，但人们对创伤后应激障碍对骨骼系统的影响一无所知。在本研究中， 我们的重点是创伤后应激障碍对骨形成的影响，因为骨骼损伤是常见的 军事人员受伤，需要康复以恢复功能， 先前的研究表明海湾战争退伍军人表现出骨形成缺陷。 此外，PTSD导致交感神经激活是公认的。 下丘脑-垂体-肾上腺（HPA）轴的变化。HPA的变化 轴可以通过调节皮质醇以及生长激素（GH）来影响骨形成， 骨骼的主要系统调节器。在PTSD诱导的分子途径方面， HPA轴的变化可能影响骨，我们认为IGF-I的作用有几个原因。第一、 IGF-I在骨形成过程中起着至关重要的作用，GH和皮质醇在骨形成过程中的作用 骨与IGF-I有关。第二，IGF-I参与介导骨骼合成代谢作用， 运动是骨骼形成的关键生理调节器。第三，我们的初步数据显示， 慢性应激抑制体内IGF-I表达和骨形成。基于这些理由， 本研究拟验证以下假设：1）PTSD影响 峰值骨量和骨质疏松症的易感性; 2）PTSD产生显着的负面影响 对骨骼响应机械应变而构建新骨的能力;以及3）PTSD效应 对骨形成的影响部分是通过下调IGF-I的作用来介导的。为了测试创伤后应激障碍- 神经内分泌激素的诱导变化将对获得 我们将青春期前的小鼠置于单一的创伤应激中，并评估 PTSD对4个月大时骨量和强度峰值的影响， 骨头已经形成。测试PTSD是否对机械负荷诱导的骨产生负面影响 形成，我们将评估创伤应激对机械负荷引起的后果 增加小鼠成骨细胞的数量和活性。胫骨轴向载荷模型将 用于评估机械负荷对创伤后应激障碍患者骨形成的合成代谢作用， 非创伤后应激障碍小鼠下一步我们将评估药物干预是否能改善PTSD 症状是有效地挽救骨骼的能力，以应对机械应变。测试 假设PTSD对骨的影响是通过降低IGF-I作用介导的，我们将 检查机械负荷诱导的表达水平变化之间的相关性 IGF系统成分和骨形成标志物。为了确定受损的因果关系， IGF-I在介导PTSD效应中的作用，我们将使用转基因小鼠模型， IGF-I的作用是挽救创伤后应激障碍对骨骼的影响。对分子的理解 创伤后应激障碍影响骨形成过程的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。

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.