Exposing Invisible Wounds: Impacts of PTSD on Bone Health

暴露看不见的伤口：创伤后应激障碍 (PTSD) 对骨骼健康的影响

• 批准号: 10481895
• 负责人: AMANDA C. LARUE
• 金额: --
• 依托单位: RALPH H JOHNSON VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-10-01 至 2026-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10481895
• 关键词: Acceleration; Address; Affect; Aging; Amendment; Animals; Attention; Automobile Driving; Awareness; Biomechanics; Bone Density; Bone Diseases; Bone Resorption; Cells; Characteristics; Chronic Disease; Classification; Clinical; Clinical Trials; Comprehensive Health Care; Conflict (Psychology); DSM-V; Data; Development; Diagnosis; Diagnostic Procedure; Disease; Disparity; Equilibrium; Etiology; Event; Exhibits; Face; Female; Flow Cytometry; Fracture; Freedom; General Population; Gulf War veteran; Health; Hematopoietic stem cells; Histology; Immunohistochemistry; In Vitro; Incidence; Inflammation; Inflammatory; Knowledge; Life; Link; MEKs; Maintenance; Mediating; Mediator; Mental Health; Meta-Analysis; Methods; Modeling; Modification; Molecular; Monitor; Morbidity - disease rate; Mus; Musculoskeletal Diseases; Neuropeptides; Osteoblasts; Osteoclasts; Osteocytes; Osteogenesis; Osteopenia; Osteoporosis; PI3K/AKT; Pathologic; Pathway interactions; Patients; Phenotype; Physiological; Play; Post-Traumatic Stress Disorders; Pre-Clinical Model; Premature Mortality; Prisoner; Proliferating; Property; Protein Tyrosine Phosphatase; Regulation; Reporting; Risk; Risk Factors; Role; Services; Sex Differences; Signal Pathway; Signal Transduction; Skeletal system; Source; Symptoms; Testing; Veterans; Vietnam; War; adjudication; biomechanical test; bisphosphonate; bone; bone health; bone loss; bone mass; bone turnover; cell type; clinical practice; clinically relevant; comorbidity; conditioned fear; experience; fracture risk; high risk; improved; in vivo; inhibitor; innovation; insight; male; mechanical properties; mesenchymal stromal cell; microCT; mouse model; neurogenesis; neurotrophic factor; new therapeutic target; novel; operation; osteoblast differentiation; osteoclastogenesis; osteogenic; osteoprogenitor cell; pharmacologic; pre-clinical; progenitor; protein phosphatase inhibitor-2; recruit; skeletal; standard of care; stem cells; substantia spongiosa; traumatic event; wound

Post-traumatic stress disorder (PTSD) is 3-4 times more prevalent in Veterans than in the general population, and this disparity is anticipated to increase due to heightened awareness, better diagnostic procedures, extension of ongoing conflicts, and prolonged, repeated deployments. PTSD has been described as a life sentence due to its association with increased risk of chronic disease, accelerated aging, and premature mortality. Most studies to date have focused on understanding the direct impacts of PTSD on mental health. Only recently has attention shifted to understanding the comorbidities that lead to this life sentence. Meta analyses suggest that low bone mass (osteopenia) and osteoporosis are significant comorbidities for patients with PTSD. Thus, identification of PTSD-related risk and subsequent mechanisms for the development of low bone mass disease is critical and highly relevant to providing comprehensive health care for our Veterans. To begin to address this growing health concern, we have established a murine model that exhibits key clinical DSM-5 characteristics of PTSD, including intrusiveness, avoidance, hyperarousal, and lasting symptoms. Using this preclinical model, we have shown that mice with a PTSD-like phenotype exhibit trabecular bone loss and decreased mechanical properties. Mechanisms driving this bone loss are unclear; however, our preliminary data implicate inflammation and the ubiquitously expressed src homology 2-containing protein tyrosine phosphatase 2 (SHP2) as drivers of PTSD-associated bone loss. SHP2 has been shown to integrate multiple signaling events across a variety of physiological and pathological functions, including inflammation, to regulate PI3K/AKT and MEK/ERK signaling. In our model of PTSD, we show SHP2 expression is increased in bone and that inhibition of SHP2 results in increased osteogenesis and decreased osteoclastogenesis in vitro and improved bone health in mice with PTSD in vivo. Based on these data, Specific Aims will test the hypothesis that PTSD negatively impacts bone health through SHP2-mediated regulation of osteogenesis and osteoclastogenesis. Aim 1 will uncover cellular mechanisms by which PTSD alters osteoblast-osteoclast balance to promote bone loss. Clinically-relevant readouts will be used to determine the comprehensive impact of PTSD on bone health. Based on our identification of hematopoietic stem cell (HSC)-derived osteoprogenitors, studies will evaluate if PTSD differentially affects osteoblastogenesis and osteoclastogenesis from multiple progenitors to lead to observed bone phenotypes. As inflammation has been shown to play a significant role in disrupting osteoclast-osteoblast equilibrium, the role of inflammation in PTSD-related bone loss will also be examined. Aim 2 will define mechanistic roles of SHP2 in PTSD-driven bone loss. This aim will determine the impact of SHP2 inhibition on progenitor cell, osteoblast, and osteoclast survival, proliferation, differentiation/maturation, and function in vitro. Both downstream effectors and upstream mediators, including inflammatory factors, will be examined. To demonstrate the functional role of SHP2 in PTSD-related bone loss, SHP099 will be delivered to mice that exhibit a PTSD-like phenotype, and effects on bone loss will be quantified and compared to standard of care bisphosphonate treatment. Given the increased incidence of PTSD in Veterans, PTSD-driven bone loss represents an important, yet underappreciated, clinical problem. Our study is significant because it is the first to test the impact of PTSD on osteogenic and osteoclastogenic progenitors and to determine if PTSD causes an imbalance of these cell types and/or inflammation through altered SHP2 signaling to cause net bone loss. Using an innovative preclinical model with high face and etiological validity, this study will provide new insight into mechanisms at the intersection of PTSD and bone health, identify unique markers for PTSD-related skeletal comorbidity, classify PTSD as a critical risk factor for bone loss and subsequent bone morbidities, inform clinical practice by increasing awareness of the importance of monitoring bone health in patients with PTSD, and define SHP2 as clinically relevant novel therapeutic target to mitigate bone loss induced by PTSD.

创伤后应激障碍（PTSD）在退伍军人中的发病率是普通人群的3-4倍， 由于意识的提高，更好的诊断程序， 持续不断的冲突和长期重复的部署。PTSD被描述为终身监禁， 它与慢性疾病、加速衰老和过早死亡的风险增加有关。大多数研究 迄今为止，人们一直专注于了解PTSD对心理健康的直接影响。直到最近才引起人们的注意 转向理解导致终身监禁的合并症。Meta分析表明，低骨量 骨质减少和骨质疏松症是PTSD患者的显著合并症。因此， PTSD相关的风险和低骨量疾病发展的后续机制是至关重要的， 为我们的退伍军人提供全面的医疗保健。 为了开始解决这一日益增长的健康问题，我们建立了一种小鼠模型， 创伤后应激障碍的DSM-5特征，包括侵入性、回避、过度觉醒和持续症状。使用 在这个临床前模型中，我们已经证明具有PTSD样表型的小鼠表现出骨小梁丢失， 机械性能下降。导致这种骨质流失的机制尚不清楚;然而，我们的初步数据显示， 暗示炎症和普遍表达的含src同源性2的蛋白酪氨酸磷酸酶2 （SHP 2）作为PTSD相关骨丢失的驱动因素。SHP 2已被证明整合多种信号事件 在各种生理和病理功能，包括炎症，调节PI 3 K/AKT和 MEK/ERK信号传导。在我们的创伤后应激障碍模型中，我们发现骨中SHP 2的表达增加， SHP 2在体外导致骨生成增加和破骨细胞生成减少，并改善骨健康。 体内PTSD小鼠。基于这些数据，具体目标将测试PTSD对创伤后应激障碍的负面影响的假设。 通过SHP 2介导的骨生成和破骨细胞生成调节骨健康。目标1将揭示 PTSD通过改变成骨细胞-破骨细胞平衡促进骨丢失的细胞机制。临床相关 读数将用于确定PTSD对骨骼健康的综合影响。根据我们的鉴定 造血干细胞（HSC）衍生的骨祖细胞，研究将评估创伤后应激障碍是否差异影响 成骨细胞生成和来自多个祖细胞的破骨细胞生成，以导致观察到的骨表型。作为 已经显示炎症在破坏破骨细胞-成骨细胞平衡中起重要作用， 还将检查PTSD相关骨丢失中的炎症。目标2将定义SHP 2在以下方面的机制作用： 创伤后应激障碍导致的骨质流失该目的将确定SHP 2抑制对祖细胞、成骨细胞和成骨细胞的影响。 体外破骨细胞存活、增殖、分化/成熟和功能。下游效应器和 将检查上游介质，包括炎症因子。证明SHP 2的功能作用 在PTSD相关的骨丢失中，SHP 099将被递送至表现出PTSD样表型的小鼠，并对 骨损失将被量化并与标准的护理双膦酸盐治疗进行比较。 鉴于退伍军人中PTSD的发病率增加，PTSD驱动的骨质流失是一个重要的，但 被低估的临床问题我们的研究意义重大，因为这是第一次测试创伤后应激障碍对 成骨细胞和破骨细胞祖细胞，并确定PTSD是否导致这些细胞类型的失衡 和/或炎症通过改变SHP 2信号传导引起净骨损失。使用创新的临床前模型 高面子和病因学的有效性，这项研究将提供新的洞察机制的交叉点， 创伤后应激障碍和骨骼健康，确定创伤后应激障碍相关骨骼并发症的独特标志物，将创伤后应激障碍分类为关键的 骨丢失和随后骨发病的风险因素，通过提高对以下方面的认识来告知临床实践： 监测PTSD患者骨骼健康的重要性，并将SHP 2定义为临床相关的新 治疗靶点，以减轻由创伤后应激障碍引起的骨丢失。