A G protein-coupled, IP3/protein kinase C pathway controlling the synthesis of phosphaturic hormone FGF23

JCI Insight. 2019 Sep 5;4(17):e125007. doi: 10.1172/jci.insight.125007.


Dysregulated actions of bone-derived phosphaturic hormone fibroblast growth factor 23 (FGF23) result in several inherited diseases, such as X-linked hypophosphatemia (XLH), and contribute substantially to the mortality in kidney failure. Mechanisms governing FGF23 production are poorly defined. We herein found that ablation of the Gq/11α-like, extralarge Gα subunit (XLαs), a product of GNAS, exhibits FGF23 deficiency and hyperphosphatemia in early postnatal mice (XLKO). FGF23 elevation in response to parathyroid hormone, a stimulator of FGF23 production via cAMP, was intact in XLKO mice, while skeletal levels of protein kinase C isoforms α and δ (PKCα and PKCδ) were diminished. XLαs ablation in osteocyte-like Ocy454 cells suppressed the levels of FGF23 mRNA, inositol 1,4,5-trisphosphate (IP3), and PKCα/PKCδ proteins. PKC activation in vivo via injecting phorbol myristate acetate (PMA) or by constitutively active Gqα-Q209L in osteocytes and osteoblasts promoted FGF23 production. Molecular studies showed that the PKC activation-induced FGF23 elevation was dependent on MAPK signaling. The baseline PKC activity was elevated in bones of Hyp mice, a model of XLH. XLαs ablation significantly, but modestly, reduced serum FGF23 and elevated serum phosphate in Hyp mice. These findings reveal a potentially hitherto-unknown mechanism of FGF23 synthesis involving a G protein-coupled IP3/PKC pathway, which may be targeted to fine-tune FGF23 levels.

Keywords: Endocrinology; G-proteins; Inositol phosphates; Nephrology; Protein kinases.

Publication types

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

MeSH terms

  • Animals
  • Bone and Bones / metabolism
  • Disease Models, Animal
  • Familial Hypophosphatemic Rickets / genetics
  • Familial Hypophosphatemic Rickets / pathology
  • Female
  • Fibroblast Growth Factor-23
  • Fibroblast Growth Factors / blood
  • Fibroblast Growth Factors / genetics
  • Fibroblast Growth Factors / metabolism*
  • GTP-Binding Proteins / metabolism*
  • Genetic Predisposition to Disease / genetics
  • Humans
  • Kidney / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Osteoblasts / metabolism
  • Osteocytes
  • Parathyroid Hormone / metabolism
  • Protein Kinase C / metabolism*
  • Protein Kinases
  • RNA, Messenger / metabolism
  • Recombinant Proteins


  • FGF23 protein, human
  • Fgf23 protein, mouse
  • Parathyroid Hormone
  • RNA, Messenger
  • Recombinant Proteins
  • Fibroblast Growth Factors
  • Fibroblast Growth Factor-23
  • Protein Kinases
  • protein kinase C kinase
  • Protein Kinase C
  • GTP-Binding Proteins