Physical loading is known to be a potent regulator of bone tissue metabolism. However, the cellular mechanisms that allow bone to sense and respond to load are not understood. Our prior work has suggested that pericellular dynamic fluid flow is an important cellular physical signal for both osteoblasts and osteocytes. Although we have elaborated many aspects of intracellular signaling activated by dynamic fluid flow, we have not uncovered the molecular mechanotransduction mechanism which initiates these signals. In this application, we propos that primary cilia are acting as cellular flow sensors and are thereby contribute to mechanotransduction in bone. We have collected unique preliminary data that suggest that primary cilia may also act as flow sensors in bone. Specifically, our results suggest that osteoblastic cells express primary cilia, that dynamic flow is able to mobilize these cilia, and that disruption of the cilia interferes with the ability of the cells to sense dynamic flow. The central hypothesis of this two year project is that dynamic fluid flow due to loading regulates bone cell metabolism via a molecular mechanism involving the primary cilia. To test this hypothesis we will undertake a series of bone in vitro and in vivo experiments to determine if primary cilia act as flow transducers in bone cells in cell culture experiments in highly controlled accurate flow conditions (aim 1), and disrupting primary cilia in vivo inhibits bone's ability to adapt to external mechanical loading (aim 2). If our hypothesis is found to be true it would represent a breakthrough and shift of paradigm in the search for the mechanism of mechanotransduction in bone. Thus, although the evidence for the primary cilia's function as a flow sensor is still relatively immature, this project has potentially profound implications for future research in terms of mechanoregulation of bone in both health and disease. The etiologies of several diseases are related to pathology in the ability of bone to adapt its structure to mechanical demand, including osteoporosis that affects over 25 million people. In this project, we focus on a novel cellular sensor, the primary cilia, which may be responsible for mechanotransduction in bone. If our hypothesis is found to be true it would represent a breakthrough and shift of paradigm in bone biology and, thus, although the evidence for the primary cilia's function as a mechanical sensor is still relatively immature, this project has potentially profound implications for future research in terms of mechanoregulation of bone in both health and disease. [unreadable] [unreadable] [unreadable]