Project 443563

Physical forces are critical for successful function of many organs including bone. Bone is formed or removed to meet changes in the local mechanical environment. Exercise is the most efficient and cost-effective intervention to improve bone health. While it is clear that physical activity can enhance bone mass, it remains unknown if the time of day at which exercise is performed can alter adaptive bone (re)modeling. Our preliminary data show that circadian rhythms affect mechanoadaptation; the time of day at which in vivo tibial loading in mice was performed had a significant impact on the adaptive cortical bone formation response, which was coincident with differential Sost expression, a powerful bone mass regulator. In this project, we combine expertise in bone mechanobiology, endocrinology, and circadian rhythm to 1) To identify time of day-dependent effects of controlled loading and exercise on bone formation, resorption, mass, microstructure, and mechanical properties. 2) To identify time of day-dependent effects of loading on gene expression and determine how the clock regulates osteocyte-related genes. 3) To resolve how disruption of peripheral clocks in osteocytes affects bone mass, microstructure, and mechanical properties. 4) To determine if disruption of peripheral clocks in osteoblasts or osteocytes alters mechanoadaptation. This study will establish if targeting physical activity to a specific time of day will help mitigate bone fracture risk. These studies will also resolve how disruption of peripheral circadian clocks in bone cells affects bone mass and microstructure and mechanoresponse. Lastly, these studies examine how the circadian clock regulates bone mass which will allow us to identify novel molecular targets that can be used as countermeasures for serious problems caused by severe lack in physical activity in elderly and paralyzed patients as well as night and rotating shift workers, who display an increased incidence of fractures.