Impaired Growth Plate Maturation in XLH Is due to Both Excess FGF23 and Decreased 1,25-Dihydroxyvitamin D Signaling

Endocrinology. 2023 Nov 20;165(1):bqad186. doi: 10.1210/endocr/bqad186.

Abstract

X-linked hypophosphatemia (XLH) is the most common form of hereditary hypophosphatemic rickets. The genetic basis for XLH is loss of function mutations in the phosphate-regulating endopeptidase X-linked (PHEX), which leads to increased circulating fibroblast growth factor 23 (FGF23). This increase in FGF23 impairs activation of vitamin D and attenuates renal phosphate reabsorption, leading to rickets. Previous studies have demonstrated that ablating FGF23 in the Hyp mouse model of XLH leads to hyperphosphatemia, high levels of 1,25-dihydroxyvitamin D, and is not associated with the development of rickets. Studies were undertaken to define a role for the increase in 1,25-dihydroxyvitamin D levels in the prevention of rickets in Hyp mice lacking FGF23. These mice were mated to mice lacking Cyp27b1, the enzyme responsible for activating vitamin D metabolites, to generate Hyp mice lacking both FGF23 and 1,25-dihydroxyvitamin D (FCH mice). Mice were fed a special diet to maintain normal mineral ion homeostasis. Despite normal mineral ions, Hyp mice lacking both FGF23 and Cyp27b1 developed rickets, characterized by an interrupted, expanded hypertrophic chondrocyte layer and impaired hypertrophic chondrocyte apoptosis. This phenotype was prevented when mice were treated with 1,25-dihydroxyvitamin D from day 2 until sacrifice on day 30. Interestingly, mice lacking FGF23 and Cyp27b1 without the PHEX mutation did not exhibit rickets. These findings define an essential PHEX-dependent, FGF23-independent role for 1,25-dihydroxyvitamin D in XLH and have important therapeutic implications for the treatment of this genetic disorder.

Keywords: FGF23; calcium; chondrocytes and rickets; phosphorus; vitamin D.

MeSH terms

  • 25-Hydroxyvitamin D3 1-alpha-Hydroxylase / genetics
  • Animals
  • Familial Hypophosphatemic Rickets* / metabolism
  • Fibroblast Growth Factors / genetics
  • Fibroblast Growth Factors / metabolism
  • Growth Plate / metabolism
  • Mice
  • Minerals / therapeutic use
  • Phosphates
  • Vitamin D / metabolism

Substances

  • 1,25-dihydroxyvitamin D
  • 25-Hydroxyvitamin D3 1-alpha-Hydroxylase
  • Fgf23 protein, mouse
  • Fibroblast Growth Factors
  • Minerals
  • Phosphates
  • Vitamin D
  • Phex protein, mouse