Exposing Invisible Wounds: Impacts of PTSD on Bone Health

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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.