The parathyroid is a target organ for FGF23 in rats

J Clin Invest. 2007 Dec;117(12):4003-8. doi: 10.1172/JCI32409.

Abstract

Phosphate homeostasis is maintained by a counterbalance between efflux from the kidney and influx from intestine and bone. FGF23 is a bone-derived phosphaturic hormone that acts on the kidney to increase phosphate excretion and suppress biosynthesis of vitamin D. FGF23 signals with highest efficacy through several FGF receptors (FGFRs) bound by the transmembrane protein Klotho as a coreceptor. Since most tissues express FGFR, expression of Klotho determines FGF23 target organs. Here we identify the parathyroid as a target organ for FGF23 in rats. We show that the parathyroid gland expressed Klotho and 2 FGFRs. The administration of recombinant FGF23 led to an increase in parathyroid Klotho levels. In addition, FGF23 activated the MAPK pathway in the parathyroid through ERK1/2 phosphorylation and increased early growth response 1 mRNA levels. Using both rats and in vitro rat parathyroid cultures, we show that FGF23 suppressed both parathyroid hormone (PTH) secretion and PTH gene expression. The FGF23-induced decrease in PTH secretion was prevented by a MAPK inhibitor. These data indicate that FGF23 acts directly on the parathyroid through the MAPK pathway to decrease serum PTH. This bone-parathyroid endocrine axis adds a new dimension to the understanding of mineral homeostasis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone and Bones / metabolism
  • Cells, Cultured
  • Early Growth Response Protein 1 / biosynthesis
  • Early Growth Response Protein 1 / genetics
  • Fibroblast Growth Factors / genetics
  • Fibroblast Growth Factors / metabolism*
  • Fibroblast Growth Factors / pharmacology
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology*
  • Glucuronidase / biosynthesis
  • Glucuronidase / genetics
  • Homeostasis / drug effects
  • Homeostasis / physiology*
  • Humans
  • Intestinal Mucosa / metabolism
  • Kidney / metabolism
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology
  • Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 1 / genetics
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 3 / genetics
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Parathyroid Glands / cytology
  • Parathyroid Glands / metabolism*
  • Parathyroid Hormone / biosynthesis*
  • Parathyroid Hormone / genetics
  • Phosphates / metabolism*
  • Protein Kinase Inhibitors / pharmacology
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Rats
  • Receptors, Fibroblast Growth Factor / genetics
  • Receptors, Fibroblast Growth Factor / metabolism
  • Vitamin D / metabolism

Substances

  • Early Growth Response Protein 1
  • Egr1 protein, rat
  • Fgf23 protein, rat
  • Parathyroid Hormone
  • Phosphates
  • Protein Kinase Inhibitors
  • RNA, Messenger
  • Receptors, Fibroblast Growth Factor
  • Vitamin D
  • Fibroblast Growth Factors
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Glucuronidase
  • klotho protein