1,25-Dihydroxyvitamin D3 regulates furin-mediated FGF23 cleavage

Area of Science:

• Endocrinology
• Molecular Biology
• Mineral Metabolism

Background:

• Intact fibroblast growth factor 23 (iFGF23) is cleaved by furin into inactive fragments.
• Vitamin D and its receptor (VDR) are implicated in regulating furin.
• The precise mechanism of vitamin D's effect on iFGF23 cleavage is not fully understood.

Purpose of the Study:

• To investigate the effect of 1,25-dihydroxyvitamin D3 [1,25(OH)2D] and VDR on furin-mediated iFGF23 cleavage.
• To elucidate the role of VDR in regulating furin expression and activity.
• To determine the impact of this pathway on serum phosphate levels.

Main Methods:

• Utilized VDR-knockout (Vdr-/-) mice and wild-type (WT) littermates.
• Employed a VDR-knockdown osteocyte cell line (OCY454).
• Assessed furin activity, iFGF23 cleavage, and gene expression.
• Performed chromatin immunoprecipitation (ChIP) assays.
• Analyzed data from a randomized clinical trial involving ergocalciferol treatment.

Main Results:

• Vdr-/- mice exhibited a 25-fold increase in iFGF23 cleavage, with elevated furin levels and activity.
• Furin inhibition normalized iFGF23 cleavage in Vdr-/- mice and VDR-knockdown cells.
• VDR directly binds to DNA upstream of the Furin gene, suppressing its transcription.
• In WT mice, furin inhibition increased iFGF23 and decreased serum phosphate.
• 1,25(OH)2D treatment reduced furin activity, decreased iFGF23 cleavage, and increased total FGF23.
• Ergocalciferol treatment in humans increased 1,25(OH)2D and decreased furin activity and iFGF23 cleavage.

Conclusions:

• 1,25(OH)2D inhibits iFGF23 cleavage through VDR-mediated suppression of Furin expression.
• This pathway provides a mechanism for vitamin D to increase phosphaturic iFGF23 levels.
• Vitamin D plays a crucial role in regulating FGF23 metabolism and phosphate homeostasis.