Translating molecular signal pathways to orthopaedic trauma care

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DESCRIPTION (provided by applicant): Orthopaedic trauma to bones, joints, and soft tissues currently involves over 3.6 million patients each year in the U.S. alone, and the number of injuries has been steadily increasing due to the aging population and increased levels of physical activity in older individuals. Problematic severe extremity trauma with bone loss has also recently increased dramatically due to vehicular and military injuries. This application focuses on three major common areas of orthopaedic trauma: articular cartilage degeneration associated with meniscal injuries, impaired fracture healing in the aging, and the unsolved problem of traumatic segmental bone loss. Two critical interacting regulatory signal pathyways are involved in the repair of orthopaedic bone and joint trauma, namely the TGF-beta/BMP pathway and the PTH/PTHrP pathway. These pathways interactively regulate differentiation of mesenchymal stem cells into bone and cartilage, control the phenotypic behavior of these tissues, and constitute a unifying theme for both the basic science and clinical components of th proposed CORT. New data implicating E3 ubiquitin ligases, Smurf 1 and Smurf2, in the control of cell phenotype through degradation of BMP and TGF-beta signaling Smads, respectively, and their regulatory interactions with PTH and inflammatory cytokines, form the basis for the basic science and clinical Project aims. The CORT will involve an Administrative Core and 4 Projects, all of which utilize the research core, a Molecular and Anatomic Imaging Core. All projects involve translational approaches with animal models of injury and repair, as well as 3 clinical studies, including an RCT of PTH in fracture healing in the aging. Project 1 evaluates the role of Smurf2 in molecular events leading to OA after meniscal injury in a murine model, and in humans. Correlation with functional and quantitative MRI outcomes in humans will be studied. Project 2 will define the role of Smurfs and PTH in a fracture model in aging mice, to determine the molecular basis for use of PTH in stimulating fracture healing in aging patients. Project 3 will evaluate teriparatide (PTH) as a therapy for acceleration of return to function and quantitative radiographic healing of low energy pelvic fractures in aging patients, based on dramatic preliminary clinical data. Project 4 involves study of the role of Smurfs and PTH modulation of gene therapy with rAAV for allograft healing in mice, and a clinical trial of new high resolution cone beam CT scans in patients to quantify allograft vs autograft healing/vascularity.