| Large bone defects caused by traumatic injury or tumor resection pose a significant clinical challenge as they cannot not heal without intervention, and current bone grafting therapies are limited. Tissue engineering is a promising alternative, but is often limited by poor recruitment or supply of endogenous progenitor cells. Unlike large defects, bone fractures heal readily by recapitulating the steps of bone development. In fracture repair, mechanical cues, in the form of interfragmentary strains, are essential to determine the pathway by which bone formation occurs, namely direct bone formation through intramembranous ossification or indirect bone formation through endochondral ossification, in which a cartilage template forms first and is later replaced by bone. The mechanisms by which osteoprogenitor cells are mobilized during bone development and how mechanical cues direct fracture repair are poorly understood. We observed combinatorial roles of the mechanosensitive transcriptional co-activators, Yes-associated protein (YAP) and Transcriptional co-activator with PDZ-motif (TAZ) in promoting both bone development and repair. The goal of this application is to define the mechanistic roles of YAP/TAZ in osteoprogenitor cell mobilization during bone development and mechanical load-mediated fracture repair. Accomplishing this goal will provide new insights into developmental bone diseases, identify pathways that could be exploited to enhance healing, and position us to design new tissue engineering strategies that recapitulate the processes of bone development and natural repair for regeneration of large bone defects. |
