Molecular Genetic Studies of Bone Mechanical Strain and of Pedigrees With Very High Bone Density

摘要

The primary goal of the proposed work is to identify the genes and their functions involved in mediating the anabolic response to mechanical stress. During the past year, we have used state-of-the-art technologies to investigate the role of a number of potential candidate genes in mediating skeletal anabolic responses to mechanical loading (ML). We found that PTN disruption in mice caused less than the anticipated decrease in the amount of new bone formed in response to ML in part because of compensation by increased expression of mid kine. To investigate the role of Rassignaling pathway in ML, we used transgeneic mice over expressing Rass F1C, and found ML-induced bone formation (BF) was increased in transgenic mice, thus suggesting a role for Rassignaling in anabolic response to ML. Based on these established importance of leptin in regulating BF, we evaluated the role of leptin signaling in mediating ML effects on bone and found that leptin-leptin receptor signaling mechanism may play a key role in determing the mechano sensitivity of osteoblasts. We believe that successful accomplishment of the proposed studies will provide a better understanding of the molecular mechanisms involved in identifying the genes and their function as related to mechanical stress.