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Pkd1 localizes to primary cilia in osteoblasts and osteocytes. Targeted deletion of  Pkd1  in osteoblasts results in osteopenia and abnormalities in Runx2-mediated osteoblast development. Kif3a, an intraflagellar transport protein required for cilia function, is also expressed in osteoblasts. To assess the relationship between Pkd1 and primary cilia function on bone development, we crossed heterozygous  Pkd1-  and  Kif3a -deficient mice to create compound  Pkd1 and Kif3a -deficient mice.  Pkd1  haploinsufficiency ( Pkd1   +/Δ ) resulted in osteopenia, characterized by decreased bone mineral density, trabecular bone volume, and cortical thickness. In addition, deficiency of Pkd1 resulted in impaired osteoblastic differentiation and enhanced adipogenesis in both primary osteoblasts and/or bone marrow stromal cell cultures. These changes were associated with decreased  Runx2  expression, increased  PPARγ  expression, and impaired hedgehog signaling as evidenced by decreased  Gli2  expression in bone and osteoblast cultures. In contrast, heterozygous  Kif3a   +/Δ  mice display no abnormalities in skeletal development or osteoblast function, but exhibited decreased adipogenic markers in bone and impaired adipogenesis  in vitro  in association with decreased  PPARγ  expression and upregulation of  Gli2 . Superimposed  Kif3a  deficiency onto  Pkd1   +/Δ  mice paradoxically corrected the effects of  Pkd1  deficiency on bone mass, osteoblastic differentiation, and adipogenesis. In addition,  Runx2 ,  PPARγ  and  Gli2  expression in bone and osteoblasts were normalized in compound double  Pkd1   +/Δ  and  Kif3a   +/Δ  heterozygous mice. The administration of sonic hedgehog, overexpression of  Gli2 , and the PC1 C-tail construct all increased  Gli2  and  Runx2 -II expression, but decreased  PPARγ 2 gene expression in C3H10T1/2 cells. Our findings suggest a role for Pkd1 and Kif3a to counterbalance the regulation of osteogenesis and adipogenesis through differential regulation of Runx2 and  PPARγ  by Gli2.

Kif3a Deficiency Reverses the Skeletal Abnormalities in Pkd1 Deficient Mice by Restoring the Balance Between Osteogenesis and Adipogenesis