Nuclear xenobiotic receptor PXR-null mouse exhibits hypophosphatemia and represses the Na/Pi-cotransporter SLC34A2

Objective We previously found that the lack of nuclear xenobiotic receptor, PXR, decreases femoral bone mineral density (BMD) in Pxr(-/-) mice. Our present study aims to elucidate the inherited phenotype that correlates with the decreased BMD and to identify the PXR-regulated gene that may link with this phenotype. Methods Pxr(+/+) and Pxr(-/-) mice were used to measure the serum levels of inorganic phosphate (Pi), calcium and vitamin D-3. Real time PCR and western blots were used to determine the intestinal and renal expressions of Pi and calcium transporters and various other genes involved in bone homeostasis. Cell-based reporter and gel shift assays were performed to characterize the promoter of the identified PXR-regulated gene. Results In both Pxr(-/-) male and female mice, lumbar, sternum, and skull were all also found to have decreased their BMD values. Serum Pi levels, but not calcium levels, are attenuated in Pxr(-/-) mice, exhibiting a phenotype of hypophosphatemia. Among the members of the Na/Pi contransporter family, only the SLC34A2 mRNA and protein are repressed in Pxr(-/-) mice. PXR can directly activate the transcription of the SLC34A2 gene through an ER6 motif on its promoter. Conclusion Pxr(-/-) mice show the inherited phenotype of hypophosphatemia. The lack of PXR results in a severe repression of the Na/Pi cotransporter NaPi-IIb/Npt2b (SLC34A2), thus leading Pxr(-/-) males and females to develop a type of hypophosphatemia. Pharmacogenetics and Genomics 20:9-17 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.