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

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

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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-Phex Δflox/y, and hyp-mice was likewise reduced compared with that in normal mice. Abnormal renal phosphate transport in Cre-Phex Δflox/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-Phex Δflox/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.

Original languageEnglish (US)
Pages (from-to)722-734
Number of pages13
JournalJournal of Clinical Investigation
Volume118
Issue number2
DOIs
StatePublished - Feb 1 2008

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ASJC Scopus subject areas

  • Medicine(all)

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Yuan, B., Takaiwa, M., Clemens, T. L., Feng, J. Q., Kumar, R., Rowe, P. S., Xie, Y., & Drezner, M. K. (2008). Aberrant Phex function in osteoblasts and osteocytes alone underlies murine X-linked hypophosphatemia. Journal of Clinical Investigation, 118(2), 722-734. https://doi.org/10.1172/JCI32702