Ablation of vitamin D signaling rescues bone, mineral, and glucose homeostasis in Fgf-23 deficient mice

Matrix Biol. 2007 Mar;26(2):75-84. doi: 10.1016/j.matbio.2006.10.003. Epub 2006 Oct 20.

Abstract

To explore further the role of the vitamin D axis for fibroblast growth factor-23 (FGF23) signaling, we mated Fgf-23 deficient (Fgf-23(-/-)) mice and vitamin D receptor (VDR) mutant mice with a non-functioning VDR. To prevent secondary hyperparathyroidism in VDR and compound mutant mice, all mice were kept on a rescue diet enriched with calcium, phosphorus, and lactose. Consistent with previous findings, Fgf-23(-/-) animals showed hypercalcemia, hyperphosphatemia, growth retardation, ectopic calcifications, severe osteoidosis, skin atrophy, and renal dysfunction. In addition, here we describe that Fgf-23(-/-) mice are hypoglycemic, and have profoundly increased peripheral insulin sensitivity and improved subcutaneous glucose tolerance, but normal renal expression of the aging suppressor gene Klotho. Although VDR and double mutants on the rescue diet still had moderately elevated parathyroid hormone serum levels and lower bone mineral density compared to wild-type mice, double mutant mice were normocalcemic and normophosphatemic, and had normal body weight, normal renal function, and no ectopic calcifications. Ablation of vitamin D signaling in compound mutants also normalized subcutaneous glucose tolerance tests and insulin secretory response. In conclusion, our results indicate that the alterations in mineral and carbohydrate metabolism present in Fgf-23(-/-) mice require an intact vitamin D signaling pathway.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Blotting, Northern
  • Bone Density
  • Bone and Bones / metabolism*
  • Calcium / metabolism*
  • Crosses, Genetic
  • DNA Primers
  • Fibroblast Growth Factors / deficiency*
  • Fibroblast Growth Factors / genetics
  • Glucose / metabolism*
  • Glucose Tolerance Test
  • Glucuronidase / metabolism
  • Homeostasis / physiology*
  • Insulin / metabolism
  • Mice
  • Mice, Knockout
  • Parathyroid Hormone / blood
  • Receptors, Calcitriol / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / physiology*
  • Vitamin D / metabolism*

Substances

  • DNA Primers
  • Insulin
  • Parathyroid Hormone
  • Receptors, Calcitriol
  • Vitamin D
  • Fibroblast Growth Factors
  • fibroblast growth factor 23
  • Glucuronidase
  • klotho protein
  • Glucose
  • Calcium