P2: Role of PTH in enhancing fracture repair in aging

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The project is based on preliminary data showing an age-related quantitative decline in fracture healing in a murine model, with reproducible findings of delayed chondrogenesis and subsequent chondrocyte hypertrophy. In addition vascularization and remodeling of the mineralized cartilage is diminished. In conjunction with this, a decline in smurf2 expression in fracture callus occurs with aging, as well as a decline in COX-2 expression. Given the known effect of smurf2 on enhancing chondrocyte maturation and mineralization, and preliminary data indicating stimulation of smurf2 expression by PTH, the effects of PTH on restoring smurf2 expression and enhancing healing of fractures in aging mice will be evaluated. Determination of the role of the target cells of the periosteum will also be investigated using allografting with periosteal cells from genetically marked donor mice. The Specific Aims are: 1. Comprehensive quantitative characterization of fracture healing in young and aging mice using histomorphometry, microCT, and biomechanical analysis will be correlated with gene expression, with focus on TGF-beta/BMP and PTH/PTHrP signaling pathways. 2. Determining the differences in the capacity of periosteal stem cells from young and old mice to initiate bone repair and the roles of COX2 and PTHrP. The reparative potential of periosteum in young and old mice will be evaluated to determine if tissue from young animals can restore fracture healing in aged mice. Based on known loss of COX-2 with aging and impaired healing in Cox-2 -/- mice, effects of periosteum from COX-2 -/- and COX-2 +/- on healing in young and old mice will be evaluated. Finally, periosteum from coHAIPTHR transgenic mice will be evaluated in aging mice to determine if PTH/PTHrP signal pathway activation can restore healing in COX-2 -/- or aging mice. Healing will be evaluated by microCT, histomorphometry, and biomechanical testing in all cases. 3. Defining the effect of PTH during the various stages of fracture repair in aged mice. Despite data and clinical use of PTH in fracture healing stimulation, there is not a clear understanding of the mechanisms involved or stage of the repair process affected by PTH. The ability to improve fracture repair in aged mice, and ability of PTH to compensate for the loss of Cox-2 will be evaluated. Effects on smurfl and 2 expression during fracture healing, about which little is currently known, will also be investigated.