Tuesday, September 26, 2023
9/26/2023
PROJECT SUMMARY There is an unmet clinical need for anabolic strategies to treat the 50 million women and men in the U.S. with severely or moderately low bone mass (osteoporosis or osteopenia, respectively). Mechanical loading is a potent, physiological means to stimulate bone formation and increase bone mass. However, with aging, humans and rodents have a decline in their ability to form bone in response to exercise and other forms of mechanical loading. The basis for this decline remains unknown. Our long-term goal is to identify key mechanisms in loading-induced bone formation in the adult skeleton so that we may inform future strategies to increase bone mass in osteoporosis. Our focus in this project is on the origin of osteoblasts that form bone in response to mechanical loading, and on the Wnt signaling pathway. We propose experiments using a physiological model of bone anabolism – murine axial tibial compression – that will extend our scientific knowledge as follows. First, we will determine the origin of osteoblasts (in young-adult and old mice) that form bone in response to in vivo mechanical loading. Modern lineage tracing and histological methods will be applied to address this basic unknown. Second, we will determine if osteoblast lineage cells in old mice are less proliferative than in young mice in response to in vivo loading. If so, this will provide motivation to develop strategies to target this deficit to enhance mechanoresponsiveness. Third, motivated by the finding that Wnts1 and 7b are highly responsive to bone mechanical loading, we will determine the role of these ligands produced by osteoblasts in loading-induced bone formation. Inducible, conditional deletion of Wnt 1 and 7b will be accomplished in adult mice, followed by mechanical loading and assessment of bone formation, cell proliferation and gene expression. If loss of Wnt 1 or 7b mimics the effects of aging, it will motivate targeted treatment strategies to rescue the mechanoresponsiveness of the aged skeleton. In summary, the decline in the anabolic response of bone to mechanical loading is a central feature of skeletal aging. The proposed studies will clarify the basis for this decline while addressing fundamental mechanisms that support loading-induced bone formation.
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