RESUMEN
Bone grafting procedures are commonly used for the repair, regeneration, and fusion of bones in in a wide range of orthopaedic surgeries, including large bone defects and spine fusion procedures. Autografts are the clinical gold standard, though recombinant human bone morphogenetic proteins (rhBMPs) are often used, particularly in difficult clinical situations. However, treatment with rhBMPs can have off-target effects and significantly increase surgical costs, adding to patients' already high economic and mental burden. Recent studies have identified that FDA-approved immunosuppressant drug, FK506 (Tacrolimus), can also activate the BMP pathway by binding to its inhibitors. This study tested the hypothesis that FK506, as a standalone treatment, could induce osteogenic differentiation of human mesenchymal stromal cells (hMSCs), as well as functional bone formation in a rat segmental bone defect model and rabbit spinal fusion model. FK506 potentiated the effect of low dose BMP-2 to enhance osteogenic differentiation and mineralization of hMSCs in vitro. Standalone treatment with FK506 delivered on a collagen sponge, produced consistent bone bridging of a rat critically-sized femoral defect with functional mechanical properties comparable to naïve bone. In a rabbit single level posterolateral spine fusion model, treatment with FK506 delivered on a collagen sponge successfully fused the L5-L6 vertebrae at rates comparable to rhBMP-2 treatment. These data demonstrate the ability of FK506 to induce bone formation in human cells and two challenging in vivo models, and indicate FK506 can be utilized either as a standalone treatment or in conjunction with rhBMP to treat a variety of spine disorders.
RESUMEN
BACKGROUND: Race-related stress (RRS) is an unrecognized source of moral injury (MI)-or the emotional and/or spiritual suffering that may emerge after exposure to events that violate deeply held beliefs. Additionally, MI has not been explored as a mechanism of risk for post-traumatic stress disorder (PTSD) in trauma-exposed civilians. We examined relations among exposure to potentially morally injurious events (moral injury exposure, MIE), related distress (moral injury distress, MID), and RRS in Black Americans. Potential indirect associations between RRS and PTSD symptoms via MID were also examined. METHODS: Black Americans (n = 228; 90.4% female; Mage = 31.6 years. SDage = 12.8 years) recruited from an ongoing study of trauma completed measures assessing civilian MIE and MID, RRS, and PTSD. Bivariate correlations were conducted with MIE and MID, and mediation analysis with MID, to examine the role of MI in the relationship between RRS and PTSD symptom severity. RESULTS: MIE was significantly correlated with cultural (r = 0.27), individual (r = 0.29), and institutional (r = 0.25) RRS; MID also correlated with cultural (r = 0.31), individual (r = 0.31), and institutional (r = 0.26) RRS (ps < 0.001). We found an indirect effect of RRS on PTSD symptoms via MID (ß = 0.10, p < 0.005). CONCLUSIONS: All types of RRS were associated with facets of MI, which mediated the relationship between RRS and current PTSD symptoms. MI may be a potential mechanism through which RRS increases the risk for PTSD in Black individuals.
