Project Summary: OA is a leading cause of chronic pain and disability in our Veterans who develop OA at significantly younger ages and in higher numbers than non-Veterans. Consequently, the disease burden of OA is disproportionately borne by Veterans and the VA Healthcare system (VAHCS). Currently there are no disease modifying anti- osteoarthritis drugs (DMOAD) due in part to a historical focus on identification and tracking of radiographic OA outcomes rather than pain and function-related disease pathways. Our integrated research program in the Treat Osteoarthritis Pain and Progression (TOPP) Collaborative Merit program will test the central hypothesis that variability in OA pain and structural progression is related to heterogeneity in the cellular and molecular responses of bone, cartilage, and synovium to inflammation and joint loading. This Collaborative Merit will pursue two overarching Specific Aims: Aim 1: To improve understanding of osteoarthritis (OA) pathogeneses to enable development of targeted therapeutic approaches, and Aim 2: To establish preclinical data for new therapeutic targets to reduce pain and prevent OA progression. Using early and late OA clinical cohorts prevalent in the VAHCS and joint injury animal models to test novel therapeutic approaches will require coordinated multidisciplinary bench to bedside work for that no single project can adequately address. Further, we will couple results from treatment efficacy of vagal nerve stimulation (VNS), targeting nerve growth factor (NGF), and targeting mast cells in preclinical OA animal models with human OA phenotyping and stratification will allow for rapid transition to clinical trials in OA and joint injury. The goal of Project 4 is to determine if transcutaneous vagal nerve stimulations (tVNS) reduces pain and prevents structural progression in acute and chronic preclinical OA models. VNS, currently FDA approved for epilepsy and depression, activates a cholingeric anti-inflammatory pathway, driving production of acetylcholine (Ach) in nerves and non- neuronal cells, and provides a strong systemic anti-inflammatory effect that reduces synovial inflammation and joint pain in mouse models of rheumatoid arthritis. Within the joint, cholinergic fibers innervate the synovium, trabecular bone, and periosteum and studies suggest that the parasympathetic nervous system modulates nociceptive pain and possibly OA pathogenesis. Nicotinic acetylcholine receptor α7 (α7NAChR) in macrophages, T cells, and chondrocytes may mediate VNS effects. Based on these and our exciting preliminary data showing improved pain after 4 weeks of VNS in the destabilized medial meniscal injury model, our hypothesis is that tVNS reduces pain and prevents structural progression in OA. We will test this hypothesis in three aims: (1) Test if tVNS reduces pain in acute and chronic mouse models of OA, (2) test if tVNS slows structural progression of acute and chronic mouse models of OA, and (3) Integrate outcom...