BCCMA: Foundational Research to Act Upon and Resist Conditions Unfavorable to Bone (FRACTURE CURB): Impacts of PTSD on Fracture Healing

Ralph H Johnson Va Medical Center, Charleston SC

Investigators

Abstract

To ensure aging Veterans remain active and mobile with as little musculoskeletal pain as possible, new approaches to the prevention of osteoporosis and promotion of timely bone regeneration following a fracture are necessary. This collaborative research study brings together a group of VA investigators with diverse perspectives, insights, models, and techniques, to synergistically attack a major clinical problem that leads to high morbidity and mortality among Veterans, a bone fracture. The overall research strategy of each integrated project is to use pre-clinical models of a disease that either weakens bone or delays bone repair, to investigate novel ways to enhance the ability of parathyroid hormone (PTH) to promote bone formation, and to assess disease and treatment effects on bone in a unified, stringent manner. Already under-diagnosed and under- treated, osteoporosis is likely to increase the number of fragility fractures being treated at VA hospitals without novel tools for early detection and novel treatment strategies that circumvent the rare but devastating side effects of current therapies that inhibit bone loss. Addressing this unmet clinical need, the overall aims are to identify therapeutic strategies to improve bone health among Veterans and to enhance the bone anabolism of PTH signaling. The collaboration will address this overarching hypothesis: health problems disproportionately affecting Veterans activate signaling pathways that increase bone resorption, suppress bone formation, or impede the transition of cartilage to bone in a fracture callus such that improvements in the clinical management of osteoporosis lie in understanding how these health problems hurt bone health. This proposal will use preclinical models of post-traumatic stress disorder (PTSD) to identify mechanisms driving impacts of PTSD on fracture repair and elucidate cell-based targets and “druggable” mechanisms for mitigation of these effects, addressing OA1 of this collaborative. PTSD is 3-4 times more prevalent in Veterans than in the general population, and this disparity is anticipated to increase. PTSD is linked to reduction in bone density, increased risk for osteoporosis, increased fracture risk, and impaired fracture healing. Identification of mechanisms driving PTSD-related impaired fracture healing is critical and highly relevant to providing comprehensive health care for our Veterans. To begin to address this knowledge gap, we have established a murine model that exhibits key clinical DSM-5 characteristics of PTSD. In this preclinical model, we show that mice with a PTSD-like phenotype exhibit trabecular bone loss, a sustained inflammatory state, and impaired osteoblastogenesis and osteoclastogenesis. We also now show impaired fracture healing in mice with PTSD. Mechanisms driving the negative impact of PTSD on fracture repair are unclear; however, our pilot data suggest a role for FK506 binding protein 51 (FKBP51), an immunophilin, in PTSD-altered osteoblast and osteoclast generation, with FKBP51 inhibition leading to improved fracture healing in PTSD mice. Our Specific Aims will test the hypothesis that that PTSD impairs fracture healing through FKBP51 and that this may be therapeutically targeted. Aim 1 will use clinically relevant readouts to elucidate how PTSD drives cellular changes to disrupt fracture healing. Aim 2 will investigate the role of FKBP51 in PTSD-altered fracture healing to determine if FKBP51 is a potential target for improved fracture repair. To demonstrate the translational potential of these studies, we will also test FKBP51-targeted interventions to improve fracture healing affected by PTSD. Given the increased incidence of PTSD in Veterans, this study is significant as it will be the first to define mechanisms by which PTSD leads to impaired fracture healing, identify cellular compartment(s) impacted by PTSD, and elucidate the role of FKBP51 in PTSD-driven impaired fracture healing. Using our innovative preclinical model with high face and etiological validity, we will provide new insight into mechanisms at the intersection of the PTSD-FKBP51-fracture axis, classify PTSD as a critical risk factor for poor fracture repair, and inform clinical practice by testing novel therapeutics to mitigate poor fracture healing induced by PTSD.