Post-traumatic osteoarthritis (PTOA) frequently develops secondary to joint injury, with clinical manifestations of pain and dysfunction lagging months to years after the injury. No effective therapies exist to prevent or slow PTOA progression, and evidence indicates interventions must occur acutely after injury to modify the disease course. The novel peptide SS-31 is a highly targeted mitoprotective therapy that has shown success in clinical trials for treatment of several diseases. This project will test the hypothesis that acute mechanical trauma induces MT dysfunction in chondrocytes that leads to PTOA, and that restoring MT bioenergetics with SS-31 will arrest the development of PTOA in vivo. First, the early (seconds to days) temporal response of cartilage to injury with respect to MT function, cell death, and matrix degradation, will be assessed to identify a therapeutic window of time for treatment of MT dysfunction after mechanical injury of cartilage. Then, the efficacy of SS-31 in mitigating the effects of cartilage injury will be studied to identify the time course in which mitoprotection can effectively inhibit MT dysfunction, restore cellular bioenergetics and prevent cell death. Finally, the effects of mitochondrial stabilization on PTOA in vivo will be assessed in the peracute to chronic phases following impact-induced cartilage damage and MT dysfunction in vivo. The results of these studies will demonstrate if mitoprotective therapies restore mitochondrial bioenergetics, prevent acute cell injury and apoptosis, and inhibit the progression of cartilage degeneration, thereby providing the first therapy to prevent PTOA. All components of this proposal reflect and support the mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Completion of the proposed project will reveal novel scientific information about the early changes in cartilage at subcellular to macroscopic resolution scales after injury. Understanding the acute post-injury pathobiology of PTOA is critical because it represents a time point where true intervention, with an aim at preventing PTOA, is possible before the disease becomes fully established. The success of SS-31 in several phase II clinical trials, where disease is already established, suggests that mitoprotection will also be an effective therapy for PTOA in those cases where OA is present at the time of diagnosis and treatment. Two PhD students will be trained in this proposal with input from a multifaceted interdisciplinary team of scientists and clinicians from the human clinical and animal models perspectives. Finally, all members of the assembled team in this proposal are well represented on national and international levels in their respective fields, and they are dedicated and experienced at dissemination of scientificinformation at meetings and in journal publications. The interdisciplinary team assembled for this project has an established collaborative relationship and brings contemporary concepts and techniques from each respective field to translate information into a realistic human clinical application to prevent PTOA.