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.

退伍军人中创伤后应激障碍 (PTSD) 的患病率是普通人群的 3-4 倍， 由于认识的提高、更好的诊断程序、扩展 持续的冲突以及长期、反复的部署。 PTSD 被描述为无期徒刑，因为 它与慢性病风险增加、加速衰老和过早死亡有关。大多数研究 迄今为止，重点是了解创伤后应激障碍（PTSD）对心理健康的直接影响。最近才受到关注 转向了解导致终身监禁的合并症。荟萃分析表明低骨 肿块（骨质减少）和骨质疏松症是 PTSD 患者的重要合并症。因此，识别 与 PTSD 相关的风险和随后发生低骨量疾病的机制至关重要且 与为退伍军人提供全面的医疗保健密切相关。 为了开始解决这一日益严重的健康问题，我们建立了一个小鼠模型，该模型表现出关键的临床特征 PTSD 的 DSM-5 特征，包括侵入性、回避性、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小梁骨丢失和 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 涉及炎症和普遍表达的含有 src 同源性 2 的蛋白酪氨酸磷酸酶 2 （SHP2）作为 PTSD 相关骨质流失的驱动因素。 SHP2 已被证明可以整合多个信号事件 跨越多种生理和病理功能，包括炎症，调节 PI3K/AKT 和 MEK/ERK 信号传导。在我们的 PTSD 模型中，我们发现骨骼中 SHP2 的表达增加，并且抑制 SHP2 导致体外成骨增加和破骨细胞生成减少，并改善骨骼健康 体内患有 PTSD 的小鼠。根据这些数据，Specific Aims 将检验 PTSD 产生负面影响的假设 通过 SHP2 介导的成骨和破骨细胞生成调节骨骼健康。目标 1 将揭开 PTSD 改变成骨细胞-破骨细胞平衡以促进骨质流失的细胞机制。临床相关 读数将用于确定创伤后应激障碍（PTSD）对骨骼健康的综合影响。根据我们的鉴定 研究将评估 PTSD 是否对造血干细胞 (HSC) 衍生的骨祖细胞产生不同影响 来自多个祖细胞的成骨细胞生成和破骨细胞生成导致观察到的骨表型。作为 炎症已被证明在破坏破骨细胞-成骨细胞平衡方面发挥着重要作用， 还将检查与 PTSD 相关的骨质流失中的炎症。目标 2 将定义 SHP2 在 创伤后应激障碍（PTSD）导致的骨质流失。该目标将确定 SHP2 抑制对祖细胞、成骨细胞和 破骨细胞在体外的存活、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。展示SHP2的功能作用 在与 PTSD 相关的骨质流失中，SHP099 将被递送至表现出 PTSD 样表型的小鼠，并对 骨质流失将被量化并与标准护理双磷酸盐治疗进行比较。 鉴于退伍军人中 PTSD 发病率的增加，PTSD 导致的骨质流失是一个重要但尚未解决的问题。 被低估的临床问题。我们的研究意义重大，因为它是第一个测试 PTSD 对 成骨和破骨祖细胞，并确定 PTSD 是否会导致这些细胞类型的不平衡 和/或通过改变 SHP2 信号传导引起的炎症导致净骨质流失。使用创新的临床前模型 这项研究具有很高的表面效度和病因学效度，将为了解这些交叉点的​​机制提供新的见解。 PTSD 和骨骼健康，识别 PTSD 相关骨骼合并症的独特标记，将 PTSD 分类为关键疾病 骨丢失和随后的骨发病的危险因素，通过提高对以下方面的认识来为临床实践提供信息 监测 PTSD 患者骨骼健康的重要性，并将 SHP2 定义为临床相关的新型药物 减轻 PTSD 引起的骨质流失的治疗目标。