Elevated fibroblast growth factor 23 exerts its effects on placenta and regulates vitamin D metabolism in pregnancy of Hyp mice

J Bone Miner Res. 2014 Jul;29(7):1627-38. doi: 10.1002/jbmr.2186.

Abstract

Fibroblast growth factor 23 (FGF23) functions in an endocrine fashion and requires α-Klotho to exert its effects on the target organs. We have recently demonstrated that the human placenta also expresses α-Klotho, which led us to hypothesize that FGF23 may exert effects on the placenta. Immunohistochemical analysis demonstrated the expression of FGF receptor 1 (FGFR1) as well as that of α-Klotho in the feto-maternal interface of both mouse and human normal-term placentas, which suggested that these areas might be receptive to FGF23. Therefore, we next investigated whether FGF23 has some roles in the placenta using Hyp mice with high levels of circulating FGF23. Hyp and wild-type (WT) females were mated with WT males, and the mothers and their male fetuses were analyzed. FGF23 levels in Hyp mothers were elevated. FGF23 levels were about 20-fold higher in Hyp fetuses than in Hyp mothers, whereas WT fetuses from Hyp mothers exhibited low levels of FGF23, as did fetuses from WT mothers. We analyzed the placental gene expression and found that the expression of Cyp24a1 encoding 25OHD-24-hydroxylase, a target gene for FGF23 in the kidney, was increased in the placentas of fetuses from Hyp mothers compared with fetuses from WT mothers. In an organ culture of WT placentas, treatment with plasma from Hyp mothers markedly increased the expression of Cyp24a1, which was abolished by the simultaneous addition of anti-FGF23 neutralizing antibody. The direct injection of recombinant FGF23 into WT placentas induced the expression of Cyp24a1. The increase in the placental expression of Cyp24a1 in fetuses from Hyp mothers resulted in decreased plasma 25-hydroxyvitamin D levels. These results suggest that increased levels of circulating FGF23 in pathological conditions such as Hyp mice exerts direct effects on the placenta and affects fetal vitamin D metabolism via the regulation of Cyp24a1 expression.

Keywords: FGF23; GENETIC ANIMAL MODELS; OSTEOMALACIA AND RICKETS; SYSTEMS BIOLOGY-BONE INTERACTORS; VITAMIN D.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 25-Hydroxyvitamin D3 1-alpha-Hydroxylase / genetics
  • 25-Hydroxyvitamin D3 1-alpha-Hydroxylase / metabolism
  • Animals
  • Antibodies, Neutralizing / pharmacology
  • Calcium / blood
  • Early Growth Response Protein 1 / metabolism
  • Familial Hypophosphatemic Rickets / blood*
  • Familial Hypophosphatemic Rickets / genetics
  • Female
  • Fetus / drug effects
  • Fetus / metabolism
  • Fibroblast Growth Factors / blood*
  • Gene Expression Regulation, Developmental / drug effects
  • Glucuronidase / genetics
  • Glucuronidase / metabolism
  • Humans
  • Kidney / embryology
  • Kidney / metabolism
  • Male
  • Maternal-Fetal Exchange / drug effects
  • Maternal-Fetal Exchange / genetics
  • Mice
  • Minerals / metabolism
  • Organ Culture Techniques
  • Phosphates / blood
  • Placenta / drug effects
  • Placenta / metabolism*
  • Pregnancy
  • Receptors, Fibroblast Growth Factor / genetics
  • Receptors, Fibroblast Growth Factor / metabolism
  • Recombinant Proteins / pharmacology
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Time Factors
  • Vitamin D / blood
  • Vitamin D / metabolism*
  • Vitamin D3 24-Hydroxylase / genetics
  • Vitamin D3 24-Hydroxylase / metabolism

Substances

  • Antibodies, Neutralizing
  • Early Growth Response Protein 1
  • Egr1 protein, mouse
  • Minerals
  • Phosphates
  • Receptors, Fibroblast Growth Factor
  • Recombinant Proteins
  • Vitamin D
  • Fibroblast Growth Factors
  • fibroblast growth factor 23
  • Vitamin D3 24-Hydroxylase
  • 25-Hydroxyvitamin D3 1-alpha-Hydroxylase
  • Glucuronidase
  • klotho protein
  • Calcium