Aberrant Phex function in osteoblasts and osteocytes alone underlies murine X-linked hypophosphatemia
Baozhi Yuan, … , Yixia Xie, Marc K. Drezner
Baozhi Yuan, … , Yixia Xie, Marc K. Drezner
Published January 2, 2008
Citation Information: J Clin Invest. 2008;118(2):722-734. https://doi.org/10.1172/JCI32702.
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Research Article Bone biology

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

Abstract

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-PhexΔflox/y mice) and conditional osteocalcin-promoted (OC-promoted) Phex inactivation in osteoblasts and osteocytes (OC-Cre-PhexΔflox/y). Serum phosphorus levels in Cre-PhexΔflox/y, OC-Cre-PhexΔflox/y, and hyp-mice were lower than those in normal mice. Kidney cell membrane phosphate transport in Cre-PhexΔflox/y, OC-Cre-PhexΔflox/y, and hyp-mice was likewise reduced compared with that in normal mice. Abnormal renal phosphate transport in Cre-PhexΔflox/y and OC-Cre-PhexΔflox/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-PhexΔflox/y, OC-Cre-PhexΔflox/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.

Authors

Baozhi Yuan, Masanori Takaiwa, Thomas L. Clemens, Jian Q. Feng, Rajiv Kumar, Peter S. Rowe, Yixia Xie, Marc K. Drezner

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Figure 3

Effects of Pi and PTH (300 μg/kg/d) stimulation on 25(OH)D-1α-hydroxylase mRNA, protein, and enzyme activity in knockout mice.

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Effects of Pi and PTH (300 μg/kg/d) stimulation on 25(OH)D-1α-hydroxylas...
(A) In the baseline state, hyp-mice and the knockouts failed to exhibit increased 25(OH)D-1α-hydroxylase activity despite significant hypophosphatemia. PTH significantly increased enzyme activity only in the normal mice and had no effect on 25(OH)D-1α-hydroxylase function in hyp-mice or both knockout mice compared with the corresponding normals. (B) In response to the prevailing hypophosphatemia in the baseline state, the hyp-mice and both knockouts manifested increased mRNA transcripts. In response to PTH stimulation, the hyp-mice and both knockouts exhibited enhancement of the mRNA transcripts similar to that observed in normal mice. (C) The increased mRNA in the hyp- and the knockout mice in the baseline state and following PTH stimulation did not result in enhanced translation of the 25(OH)D-1α-hydroxylase protein when compared with the corresponding normal mice. *P < 0.05, **P < 0.01 compared with corresponding normal mice.