Extrarenal Functions of Polycystin-1

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DESCRIPTION (provided by applicant): Pkd1 encodes PC1, a transmembrane receptor-like protein, and Pkd2 encodes PC2, a calcium channel, which interact to form functional polycystin complexes that are widely expressed in many tissues and cell types. Inactivating mutations of PKD1 or PKD2 genes cause Autosomal Dominant Polycystic Kidney Disease (ADPKD). Studies of ADPKD have elucidated the functions of polycystins and their interdependence on primary cilia in renal epithelial cells; however, they have provided only a limited window into the potential broader functions of polycystins/primary cilia complexes in other tissues, such as bone. We have found that Pkd1 and Pkd2, as well as primary cilia are present in osteoblasts and osteocytes, that primary osteoblasts derived from Pkd1 null mice have impaired osteoblast differentiation capacity and a propensity to differentiate in to adipocytes in vitro, and that conditional deletion of Pkd1 in mature osteoblasts of mice results in osteopenia due to impaired osteoblast-mediated bone formation that is also associated with increased bone marrow adipogenesis in vivo. These findings suggest that polycystins and primary cilia have important biological function in bone. To further examine the skeletal functions of polycystins, we will use osteoblast-lineage specific promoter-Cre mice to selectively delete Pkd1 and Pkd2 from different stages within the osteoblastic lineage, including pre-osteoblasts, mature osteoblasts and osteocytes. To explore potential interdependence of polycystin and primary cilia in bone, we will examine the effect of bone-specific deletion of Kif3a to disrupt primary cilia formation in the osteoblastic lineage. We propose the hypothesis that the loss of polycystins results in the inability of pre-osteoblasts, mature osteoblasts, and osteocytes to maintain their stage of differentiation and survival, resulting in cells reverting to a proliferative, less differentiated state and responding abnormally to the multitude of environmental clues affecting skeletal development and bone formation postnatally. Overall, our studies will define the polycystin/primary cilium complex as a new anabolic pathway in bone as well as possibly provide a new target for developing anabolic agents to treat osteoporotic disorders. In addition, a greater knowledge of specific functions of polycystins in bone will help clarify their overall functions that will translate back to the kidney and other tissues.