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 D3. 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.


CONCLUSIONS
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.
Konno
Yoshihiro
Y
Pharmacogenetics Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, North Carolina 27709, USA.
Moore
Rick
R
Kamiya
Nobuhiro
N
Negishi
Masahiko
M
D000818:Animals; D015153:Blotting, Western; D015519:Bone Density / Q000235:genetics; D002118:Calcium / Q000097:blood; D002762:Cholecalciferol / Q000097:blood; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D017674:Hypophosphatemia / Q000235:genetics*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D010641:Phenotype; D010710:Phosphates / Q000097:blood; D000077297:Pregnane X Receptor; D011401:Promoter Regions, Genetic / Q000235:genetics; D011987:Receptors, Steroid / Q000235:genetics / Q000502:physiology*; D050614:Sodium-Phosphate Cotransporter Proteins, Type IIb / Q000096:biosynthesis* / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics
D010710:Phosphates; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; C493558:Slc34a2 protein, mouse; D050614:Sodium-Phosphate Cotransporter Proteins, Type IIb; D002762:Cholecalciferol; D002118:Calcium