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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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 5

Bone histomorphology in normal, hyp-, Cre-PhexΔflox/y, and OC-Cre-PhexΔflox/y mice.

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Serum phosphatonin levels in normal, hyp-, OC-Cre-PhexΔflox/y, and Cre-P...
(A) Goldner-stained sections of cortical bone reveal at low magnification an apparent increase in unmineralized osteoid (red-brown colored) in the hyp-, Cre-PhexΔflox/y, and OC-Cre-PhexΔflox/y mice, compared with that in normals. At higher magnification, the evident increased unmineralized osteoid in the cortical bone specimens from the hyp-, Cre-PhexΔflox/y, and OC-Cre-PhexΔflox/y mice appears comparable in magnitude. (B) The double-labeled bone specimens, viewed under fluorescent light, show normal mineralization in the normal mice, manifested by distinct dual labels deposited beneath narrow osteoid seams. In contrast, the bone sections from the hyp-, Cre-PhexΔflox/y, and OC-Cre-PhexΔflox/y mice have diffuse smudged fluorescent labels under widened osteoid seams, indicating a disorderly deposition of mineral characteristic of osteomalacia. The diffuse patchy double labels were too indistinct to permit quantitative assessment of the abnormal mineralization dynamics. (C) Quantitative histological exam of the Goldner-stained sections from a minimum of 6 animals in each group revealed significantly increased osteoid surface and osteoid volume in the hyp-, Cre-PhexΔflox/y, and OC-Cre-PhexΔflox/y mice, as indicated by the asterisks denoting statistically significant values (***P < 0.001). In contrast, there was no significant difference in these values in the knockout models and the hyp-mice (denoted by the black columns), again providing evidence that the osteomalacia was of comparable magnitude in these animal models.