The rate of bone repair slows with aging, and little is known about the mechanisms responsible for this delayed repair process. The slow healing is responsible for increased morbidity and even mortality when older adults sustain a fracture. During fracture repair, undifferentiated mesenchymal cells accumulate and differentiate to osteoblasts to reestablish the mechanical properties of bone. We discovered that ?-catenin needs to be precisely regulated for normal fracture repair, and both up and down regulation inhibit the ability of cells to become osteoblasts. ?-catenin protein level was substantially increased during fracture repair with aging, and this was associated with an inhibition of undifferentiated cells to become osteoblasts. Furthermore, we found that hematopoetic cells from young mice could suppress ?-catenin and rejuvenate repair. Here we will use heterochronic parabiosis experiments, in which young and old mice share a blood supply, and bone marrow transplantation experiments to identify the cell type responsible for the rejuvenation effect. Furthermore, we will study the role of secreted factors produced by young hematopoetic cells, that we identified using mass spectroscopy, in bone repair in aging using genetically modified mice. This work will identify novel potential therapies to improve fracture repair in aging, ultimately reducing the morbidity associated with injury in older individuals.
As we age, the rate of fracture healing slows, and the complications associated with poor healing increase. Despite the demonstration of delayed fracture repair with aging, little is known about the mechanisms responsible for this delayed repair process. We found that circulating factors from young animals can rescue to delayed fracture repair characteristic of older animals. The data generated in this proposal will build on this information to identify the mechanism causing delayed fracture repair in aging and the role of circulating factors in this process. This work will also suggest an effective and safe therapeutic approach to treat or prevent fracture healing complications in aging.
