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Aberrant Phex function in osteoblasts and osteocytes alone underlies murine X-linked hypophosphatemia.

Patients with X-linked hypophosphatemia (XLH) and the hyp-mouse, a model of XLH characterized by a deletion in the Phex gene, manifest hypophosphatemia, renal phosphate wasting, and rickets/osteomalacia. Cloning of the PHEX/Phex gene and mutations in affected patients and hyp-mice established that alterations in PHEX/Phex expression underlie XLH. Although PHEX/Phex expression occurs primarily in osteoblast lineage cells, transgenic Phex expression in hyp-mouse osteoblasts fails to rescue the phenotype, suggesting that Phex expression at other sites underlies XLH. To establish whether abnormal Phex in osteoblasts and/or osteocytes alone generates the HYP phenotype, we created mice with a global Phex knockout (Cre-PhexDeltaflox/y mice) and conditional osteocalcin-promoted (OC-promoted) Phex inactivation in osteoblasts and osteocytes (OC-Cre-PhexDeltaflox/y). Serum phosphorus levels in Cre-PhexDeltaflox/y, OC-Cre-PhexDeltaflox/y, and hyp-mice were lower than those in normal mice. Kidney cell membrane phosphate transport in Cre-PhexDeltaflox/y, OC-Cre-PhexDeltaflox/y, and hyp-mice was likewise reduced compared with that in normal mice. Abnormal renal phosphate transport in Cre-PhexDeltaflox/y and OC-Cre-PhexDeltaflox/y mice was associated with increased bone production and serum FGF-23 levels and decreased kidney membrane type IIa sodium phosphate cotransporter protein, as was the case in hyp-mice. In addition, Cre-PhexDeltaflox/y, OC-Cre-PhexDeltaflox/y, and hyp-mice manifested comparable osteomalacia. These data provide evidence that aberrant Phex function in osteoblasts and/or osteocytes alone is sufficient to underlie the hyp-mouse phenotype.

Pubmed ID: 18172553

Authors

  • Yuan B
  • Takaiwa M
  • Clemens TL
  • Feng JQ
  • Kumar R
  • Rowe PS
  • Xie Y
  • Drezner MK

Journal

The Journal of clinical investigation

Publication Data

February 4, 2008

Associated Grants

  • Agency: NCRR NIH HHS, Id: 1K12RR017614
  • Agency: NIAMS NIH HHS, Id: 5R01-AR051598-05
  • Agency: NIDCR NIH HHS, Id: 7R03-DE015900-03
  • Agency: NCRR NIH HHS, Id: M01-RR03186-21
  • Agency: NIAMS NIH HHS, Id: P30-AR046031
  • Agency: NIAMS NIH HHS, Id: R01 AR051598
  • Agency: NIDDK NIH HHS, Id: R01 DK076829
  • Agency: NIAMS NIH HHS, Id: R01-AR27032-26
  • Agency: NIAMS NIH HHS, Id: R01-AR49410
  • Agency: NIDDK NIH HHS, Id: R01-DK65830
  • Agency: PHS HHS, Id: R01-SK65830-1
  • Agency: NIDDK NIH HHS, Id: R21 DK077669

Mesh Terms

  • Animals
  • Biological Transport
  • Bone and Bones
  • Disease Models, Animal
  • Familial Hypophosphatemic Rickets
  • Femur
  • Fibroblast Growth Factors
  • Genetic Diseases, X-Linked
  • Kidney
  • Mice
  • Mice, Knockout
  • Osteoblasts
  • Osteocytes
  • PHEX Phosphate Regulating Neutral Endopeptidase
  • Phosphorus
  • Vitamin D