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J. Biol. Chem., Vol. 283, Issue 18, 12624-12634, May 2, 2008

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Polycystin-1 Regulates Skeletogenesis through Stimulation of the Osteoblast-specific Transcription Factor RUNX2-II^*

From the Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas 66160

Polycystin-1 (PC1) may play an important role in skeletogenesis through regulation of the bone-specific transcription factor Runx2-II. In the current study we found that PC1 co-localizes with the calcium channel polycystin-2 (PC2) in primary cilia of MC3T3-E1 osteoblasts. To establish the role of Runx2-II in mediating PC1 effects on bone, we crossed heterozygous Pkd1^m1Bei and Runx2-II mice to create double heterozygous mice (Pkd1^+/m1Bei/Runx2-II^+/-) deficient in both PC1 and Runx2-II. Pkd1^+/m1Bei/Runx2-II^+/- mice exhibited additive reductions in Runx2-II expression that was associated with impaired endochondral bone development, defective osteoblast-mediated bone formation, and osteopenia. In addition, we found that basal intracellular calcium levels were reduced in homozygous Pkd1^m1Bei osteoblasts. In contrast, overexpression of a PC1 C-tail construct increased intracellular calcium and selectively stimulated Runx2-II P1 promoter activity in osteoblasts through a calcium-dependent mechanism. Site-directed mutagenesis of critical amino acids in the coiled-coil domain of PC1 required for coupling to PC2 abolished PC1-mediated Runx2-II P1 promoter activity. Additional promoter analysis mapped the PC1-responsive region to the "osteoblast-specific" enhancer element between -420 and -350 bp that contains NFI and AP-1 binding sites. Chromatin immunoprecipitation assays confirmed the calcium-dependent binding of NFI to this region. These findings indicate that PC1 regulates osteoblast function through intracellular calcium-dependent control of Runx2-II expression. The overall function of the primary cilium-polycystin complex may be to sense and transduce environmental clues into signals regulating osteoblast differentiation and bone development.

Received for publication, December 20, 2007 , and in revised form, February 25, 2008.

^* This work was supported by National Institutes of Health Grants R01-AR049712 and P50-DK057301. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: University of Kansas Medical Center, MS 3018, 3901 Rainbow Blvd., 6018 Wahl Hall East, Kansas City, KS 66160. Tel.: 913-588-9252; Fax: 913-588-9251; E-mail: dquarles{at}kumc.edu.

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