X-linked Vitamin D-resistant rickets: is bone PHEX guilty?

X-linked hypophosphatemia (XLH) is the archetypal vitamin D–resistant disease in humans, and the most common form of inherited rickets, with an incidence of approximately 1 in 20 000 live births. The disease is characterized by renal phosphate (Pi) wasting with resulting hypophosphatemia, abnormal vitamin D metabolism, defective bone and cartilage mineralization, dentine defects, and stunted growth. Recently, the gene involved in the pathogenesis of XLH was identified and designated as PHEX (the phosphate-regulating gene with homologies to endopeptidases on the X chromosome). The murine homolog of the human disease, the hyp-mouse, has a phenotype identical to that evident in patients with XLH, and is due to a large deletion in the 3′ region of the Phex gene. These findings suggest that a mutation in the PHEX/Phex gene is responsible for the phenotypic changes in patients with XLH and the hyp-mouse. 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, the authors of a recent study [1] created mice with a global Phex knockout and conditional osteocalcin-promoted (OC-promoted) Phex inactivation in osteoblasts and osteocytes. Serum phosphorus levels in both mouse strains and hyp-mice were lower than those in normal mice. Kidney cell membrane phosphate transport in all three strains was likewise reduced compared with that in normal mice. Abnormal renal phosphate transport in global or targeted Phex knockout 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, knockout mice 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. Further studies are required to elucidate the precise function of PHEX in the bones of patients suffering from vitamin D-resistant diseases.

1. Yuan B et al. J Clin Invest. 2008;118:722-734.