Inflammation and functional iron deficiency regulate fibroblast growth factor 23 production

Valentin David*, Aline Martin, Tamara Isakova, Christina Spaulding, Lixin Qi, Veronica Ramirez, Kimberly B. Zumbrennen-Bullough, Chia Chi Sun, Herbert Y. Lin, Jodie L. Babitt, Myles Wolf

*Corresponding author for this work

Research output: Contribution to journalArticle

181 Scopus citations

Abstract

Circulating levels of fibroblast growth factor 23 (FGF23) are elevated in patients with chronic kidney disease (CKD), but the mechanisms are poorly understood. Here we tested whether inflammation and iron deficiency regulate FGF23. In wild-type mice, acute inflammation induced by single injections of heat-killed Brucella abortus or interleukin-1β (IL-1β) decreased serum iron within 6 h, and was accompanied by significant increases in osseous Fgf23 mRNA expression and serum levels of C-terminal FGF23, but no changes in intact FGF23. Chronic inflammation induced by repeated bacteria or IL-1β injections decreased serum iron, increased osseous Fgf23 mRNA, and serum C-terminal FGF23, but modestly increased biologically active, intact FGF23 serum levels. Chronic iron deficiency mimicked chronic inflammation. Increased osseous FGF23 cleavage rather than a prolonged half-life of C-terminal FGF23 fragments accounted for the elevated C-terminal FGF23 but near-normal intact FGF23 levels in inflammation. IL-1β injection increased Fgf23 mRNA and C-terminal FGF23 levels similarly in wildtype and Col4a3ko mice with CKD but markedly increased intact FGF23 levels only in the CKD mice. Inflammation increased Fgf23 transcription by activating Hif1α signaling. Thus, inflammation and iron deficiency stimulate FGF23 production. Simultaneous upregulation of FGF23 cleavage in osteocytes maintains near-normal levels of biologically active, intact circulating FGF23, whereas downregulated or impaired FGF23 cleavage may contribute to elevated intact serum FGF23 in CKD.

Original languageEnglish (US)
Pages (from-to)135-146
Number of pages12
JournalKidney international
Volume89
Issue number1
DOIs
StatePublished - Jan 1 2016

Keywords

  • FGF23
  • anemia
  • bone
  • hypoxia
  • inflammation
  • mineral metabolism

ASJC Scopus subject areas

  • Nephrology

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    David, V., Martin, A., Isakova, T., Spaulding, C., Qi, L., Ramirez, V., Zumbrennen-Bullough, K. B., Sun, C. C., Lin, H. Y., Babitt, J. L., & Wolf, M. (2016). Inflammation and functional iron deficiency regulate fibroblast growth factor 23 production. Kidney international, 89(1), 135-146. https://doi.org/10.1038/ki.2015.290