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.

Public Health Relevance

We have discovered that polycystins and primary cilia play important roles in skeletal development and postnatal bone function through mouse genetic studies that conditionally deleted Pkd1 and Kif3a from the osteoblast lineage in vivo. These findings suggest that the primary cilium/polycystin complex acts as a hub to sense environmental clues and translate them into multiple signaling pathways that sustain osteoblastic development and sustain the differentiated state of mature osteoblast, which lead to a net positive effect on bone mass;and as such, represent a new area of bone biology and an identification of a novel molecular target to design anabolic treatments for osteopenic disorders. In addition, a greater knowledge of polycystins and primary cilia functions in a different cellular context could translate into a broader understanding of their functions in the kidney.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK083303-02
Application #
8097524
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Rasooly, Rebekah S
Project Start
2010-07-01
Project End
2015-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
2
Fiscal Year
2011
Total Cost
$304,029
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
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