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 project entitled “PTH receptor Signaling and Diabetes-Induced Bone Disease” will test the hypothesis that that diabetes (DM) triggers Nox-mediated ROS distress and cholesterol accumulation in bone, which impact bone formation and material properties; and that these effects are reversed by activation of the PTH Receptor (PTH1R)/SIK axis in osteocytes. This hypothesis will be tested using a preclinical model of established DM, bones from diabetic patients, FDA-approved PTH1R ligands PTH and ABL, the orally available SK-124 inhibitor, and molecular, cellular, and tissue level advanced approaches. Aim 1 will establish the contribution of Nox/ROS distress and cellular cholesterol accumulation to DM bone disease. We will determine whether DM-induced bone disease is prevented 1a) by interfering with p22phox-Nox-mediated ROS in mice with loss of function of the CYBA gene/p22phox protein and/or 1b) by increasing ABCA1-mediated cholesterol efflux pharmacologically with the liver X receptor (LXR) agonist GW3965. Aim 2 will identify the target cell(s) in bone mediating the crosstalk between DM and PTH1R/SIK axis. We will establish cell population profiles, gene expression, and function/pathway enrichment analysis in bone and bone marrow cells, separately, by single ...