Coupling fibroblast growth factor 23 production and cleavage

Iron deficiency, rickets, and kidney disease

Myles Wolf, Kenneth White

Research output: Contribution to journalArticle

74 Citations (Scopus)

Abstract

High levels of fibroblast growth factor 23 (FGF23) cause the rare disorders of hypophosphatemic rickets and are a risk factor for cardiovascular disease and death in patients with chronic kidney disease (CKD). Despite major advances in understanding FGF23 biology, fundamental aspects of FGF23 regulation in health and in CKD remain mostly unknown. RECENT FINDINGS: Autosomal dominant hypophosphatemic rickets (ADHR) is caused by gain-of-function mutations in FGF23 that prevent its proteolytic cleavage, but affected individuals experience a waxing and waning course of phosphate wasting. This led to the discovery that iron deficiency is an environmental trigger that stimulates FGF23 expression and hypophosphatemia in ADHR. Unlike osteocytes in ADHR, normal osteocytes couple increased FGF23 production with commensurately increased FGF23 cleavage to ensure that normal phosphate homeostasis is maintained in the event of iron deficiency. Simultaneous measurement of FGF23 by intact and C-Terminal assays supported these breakthroughs by providing minimally invasive insight into FGF23 production and cleavage in bone. These findings also suggest a novel mechanism of FGF23 elevation in patients with CKD, who are often iron deficient and demonstrate increased FGF23 production and decreased FGF23 cleavage, consistent with an acquired state that mimics the molecular pathophysiology of ADHR. SUMMARY: Iron deficiency stimulates FGF23 production, but normal osteocytes couple increased FGF23 production with increased cleavage to maintain normal circulating levels of biologically active hormone. These findings uncover a second level of FGF23 regulation within osteocytes, failure of which culminates in elevated levels of biologically active FGF23 in ADHR and perhaps CKD.

Original languageEnglish
Pages (from-to)411-419
Number of pages9
JournalCurrent Opinion in Nephrology and Hypertension
Volume23
Issue number4
DOIs
StatePublished - 2014

Fingerprint

Deficiency Diseases
Rickets
Kidney Diseases
Iron
Osteocytes
Chronic Renal Insufficiency
fibroblast growth factor 23
Phosphates
Hypophosphatemic Rickets
Hypophosphatemia

Keywords

  • Autosomal dominant hypophosphatemic rickets
  • Chronic kidney disease
  • Fibroblast growth factor 23
  • Iron
  • Iron deficiency
  • Osteocyte
  • Phosphate
  • Rickets

ASJC Scopus subject areas

  • Nephrology
  • Internal Medicine

Cite this

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