Clinical premise: Aging is associated with increased frequency of fragility fractures, which often result in significant economic and emotional burden. Ineffective treatment of these fractures leads to lost productivity and often increased expenses of fracture-associated complications, including increased mortality. Moreover, the risk of impaired or delayed bony union is further enhanced by patient co-morbidities and metabolic diseases such as diabetes or osteoporosis. The vast majority of these fractures target the vertebrae, proximal femur, distal femur, proximal humerus and distal radius. Whether they are treated operatively (i.e. nailing a femur fracture or plating a distal radius fracture) or non-operatively (i.e. cast or sling), these fractures heal via endochondral ossification in a process called secondary fracture healing. Various bone anabolic drugs, which were initially designed to treat osteoporotic patients, have been tested to enhance fracture repair. However, despite their established efficacy in increasing homeostatic bone mass, limited success was achieved in their clinical use to accelerate fracture repair. Therefore, identifying novel molecular targets to enhance secondary bone repair remains of paramount importance. The objective of this translational research application is to accelerate secondary bone repair in vivo by targeting novel regulatory pathways in aging mice that enhance periosteal cell-induced osteogenesis and angiogenesis during fracture callus formation. Scientific premise: We provide compelling preliminary evidence of the following: 1. Runx3 is expressed in mesenchymal cells of both human and murine fractures. 2. Runx3 expression in the callus decreases as the fracture heals. 3. Conditional deletion of Runx3 in periosteal cells (cKO) results in enhanced secondary bone healing through increased osteogenesis and angiogenesis. 4. Runx3 deletion in the periosteum resulted in increased expression of IL-17a receptor (IL-17ra) in fractured femurs of cKO mice compared to controls animals. 5. Runx3 directly binds to the proximal promoter of IL-17ra. Finally, 6. Runx3 protein levels remain elevated in mesenchymal cells in fracture calluses of aged compared to juvenile mice. Our central hypothesis is that repression of Runx3 in periosteal cells will accelerate secondary fracture healing in aging mice through activation of IL-17 signaling in mesenchymal cell populations. Specific objectives: We will establish that Runx3 deletion in periosteal cells accelerates bone regeneration and secondary bone healing in aging mice through enhanced bone formation and angiogenesis at the fracture site. (Aim 1). We will then demonstrate that Runx3 delays callus bone formation and vascular invasion by age- dependently inhibiting IL-17ra signaling in mesenchymal cells. (Aim 2A). Finally, we will use hydrogels to locally deliver Runx3 siRNA-complexed nanoparticles and examine the efficacy and safety of this therapeutic approach in accelerati...