Exposing Invisible Wounds: Impacts of PTSD on Bone Health

创伤后应激障碍(PTSD)在退伍军人中的患病率是普通人群的3-4倍， 由于提高了认识，更好的诊断程序，扩展，这种差距预计会扩大 持续不断的冲突和长期、重复的部署。创伤后应激障碍被描述为无期徒刑，因为 它与慢性病、加速衰老和过早死亡的风险增加有关。大多数研究都是为了 Date的重点是了解创伤后应激障碍对心理健康的直接影响。直到最近才引起人们的注意 转向了解导致这一无期徒刑的并发症。Meta分析表明低骨 肿块(骨量减少)和骨质疏松症是创伤后应激障碍患者的重要并发症。因此，确定 创伤后应激障碍相关风险和随后发生低骨量疾病的机制是至关重要的， 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增长的健康问题，我们建立了一个小鼠模型，显示了关键的临床 创伤后应激障碍的DSM-5特征，包括侵扰性、回避、高度觉醒和持久症状。vbl.使用 在这个临床前模型中，我们已经表明，具有PTSD样表型的小鼠表现为骨小梁丢失和 机械性能下降。导致骨质流失的机制尚不清楚；然而，我们的初步数据 与炎症和普遍表达的src同源蛋白酪氨酸磷酸酶2有关 (Shp2)作为创伤后应激障碍相关骨丢失的驱动因素。Shp2已经被证明整合了多个信令事件 通过多种生理和病理功能，包括炎症，调节PI3K/AKT和 MEK/ERK信号转导。在我们的创伤后应激障碍模型中，我们发现SHP2在骨骼中的表达增加，而抑制SHP2的表达 Shp2在体外增加成骨和减少破骨细胞生成，改善骨健康 体内存在创伤后应激障碍的小鼠。基于这些数据，特定的目标将检验创伤后应激障碍负面影响的假设 通过SHP2介导的骨生成和破骨细胞生成调节的骨健康。目标1将揭开 创伤后应激障碍改变成骨细胞-破骨细胞平衡以促进骨丢失的细胞机制。与临床相关 读数将被用来确定创伤后应激障碍对骨骼健康的综合影响。根据我们的身份证明 关于造血干细胞(HSC)来源的骨祖细胞，研究将评估创伤后应激障碍是否对 来自多个祖细胞的成骨细胞分化和破骨细胞分化导致观察到的骨表型。AS 炎症已被证明在破坏破骨细胞-成骨细胞平衡中发挥重要作用，其作用是 与创伤后应激障碍相关的骨丢失的炎症也将被检查。目标2将定义SHP2在 创伤后应激障碍导致的骨质流失。这一目标将确定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 包括炎症因子在内的上游介质将被检查。演示SHP2的功能作用 在与创伤后应激障碍相关的骨丢失中，SHP099将被传递给表现出创伤后应激障碍样表型的小鼠，并对 骨丢失将被量化，并与双磷酸盐治疗的护理标准进行比较。 考虑到退伍军人创伤后应激障碍的发生率增加，由创伤后应激障碍导致的骨丢失是一个重要的 被低估的临床问题。我们的研究意义重大，因为它是第一次测试创伤后应激障碍对 成骨和破骨祖细胞，并确定创伤后应激障碍是否会导致这些细胞类型的失衡 和/或炎症通过改变SHP2信号导致净骨丢失。使用创新的临床前模式 这项研究具有较高的表面和病因学有效性，将为研究交叉点的机制提供新的见解。 创伤后应激障碍与骨骼健康，确定创伤后应激障碍相关骨骼共病的独特标记物，将创伤后应激障碍归类为危重 骨丢失和随之而来的骨病的危险因素，通过提高对以下方面的认识来告知临床实践 监测创伤后应激障碍患者骨健康的重要性，并将SHP2定义为临床相关新报道 治疗的目标是减轻创伤后应激障碍引起的骨丢失。

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.