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.

在退伍军人中，创伤后应激障碍（PTSD）的普遍性比普通人群高3-4倍 而且由于意识提高，更好的诊断程序，扩展，预计这种差异会增加 持续的冲突，延长，重复的部署。 PTSD被描述为由于 它与慢性疾病，加速衰老和过早死亡的风险增加。大多数研究 日期专注于理解PTSD对心理健康的直接影响。直到最近才受到关注 转向理解导致这种终身监禁的合并症。元分析表明低骨头 对于PTSD患者而言，质量（骨质减少）和骨质疏松症是显着的合并症。因此，识别 PTSD相关的风险和后续发展的低骨肿块疾病的机制至关重要，并且 与为我们的退伍军人提供全面的医疗保健高度相关。 为了开始解决这一日益严重的健康问题，我们建立了一种鼠模型，展示了关键的临床 DSM-5 PTSD的特征，包括侵入性，避免，高音和持久症状。使用 这个临床前模型，我们已经表明，具有PTSD样表型的小鼠表现出小梁骨质流失和 机械性能降低。驱动骨质流失的机制尚不清楚。但是，我们的初步数据 暗示炎症和普遍表达的SRC同源性2含蛋白酪氨酸磷酸酶2 （SHP2）作为PTSD相关骨质流失的驱动因素。 SHP2已显示用于整合多个信号事件 在包括炎症在内的各种生理和病理功能，以调节PI3K/AKT和 MEK/ERK信号。在我们的PTSD模型中，我们表明骨骼中的SHP2表达增加了，并且抑制 SHP2导致体外成骨和骨质核切形成降低，并改善了骨骼健康 带有PTSD的小鼠体内。基于这些数据，具体目的将检验PTSD对负面影响的假设 通过SHP2介导的成骨和破骨细胞生成的调节，骨骼健康。 AIM 1将发现 PTSD通过改变成骨细胞骨化细胞平衡以促进骨质流失的细胞机制。临床上有关联 读数将用于确定PTSD对骨骼健康的全面影响。根据我们的身份 造血干细胞（HSC）衍生的骨基因生成剂的研究，研究将评估PTSD是否差异影响 多个祖细胞的成骨细胞生成和破骨细胞发生，导致观察到的骨表型。作为 炎症已被证明在破坏破骨细胞骨细胞平衡方面起着重要作用。 还将检查与PTSD相关的骨质流失中的炎症。 AIM 2将定义SHP2的机械作用 PTSD驱动的骨质流失。该目标将确定SHP2抑制对祖细胞，成骨细胞和 破骨细胞存活，增殖，分化/成熟和体外功能。下游效应子和 将检查上游介体，包括炎症因素。证明SHP2的功能作用 在与PTSD相关的骨质流失中，SHP099将递送到表现出PTSD样表型的小鼠，并对对 骨质流失将被量化，并将其与双膦酸盐治疗标准进行比较。 考虑到退伍军人中PTSD的发生率增加，PTSD驱动的骨质流失代表了一个重要但 未被充分考虑的临床问题。我们的研究很重要，因为它是第一个测试PTSD对 成骨和破骨构成祖细胞，并确定PTSD是否引起这些细胞类型的失衡 和/或通过改变SHP2信号传导的炎症，导致净骨质流失。使用创新的临床前模型 凭借高面和病因的有效性，本研究将为机制提供新的见解。 PTSD和骨骼健康，确定与PTSD相关骨骼合并症的独特标记，将PTSD分类为关键 骨质流失和随后的骨病的危险因素，通过提高对临床实践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SHP2定义为临床相关的新型 治疗靶标可减轻PTSD诱导的骨质流失。