JCI Insight · 12 authors, 4 centres
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This study uses mouse models and a cell line to show that vitamin D signaling via the vitamin D receptor (VDR) suppresses the expression of the protease furin, which cleaves the hormone FGF23. This inhibition of furin leads to less breakdown of FGF23, resulting in higher levels of the intact, active hormone.
The study investigates how 1,25-dihydroxyvitamin D (1,25(OH)2D) regulates the cleavage of intact FGF23 (iFGF23) by the protease furin. Using Vdr-knockout mice and a Vdr-knockdown osteocyte cell line, the researchers found that VDR deficiency leads to increased furin expression and activity, which enhances iFGF23 cleavage. This was confirmed by showing that pharmacological furin inhibition blocked the increase in cleavage. Chromatin immunoprecipitation identified VDR binding to a regulatory region upstream of the Furin gene, suggesting VDR directly suppresses Furin transcription. In wild-type mice, furin inhibition reduced cleavage, increased iFGF23, and lowered serum phosphate. Similarly, 1,25(OH)2D treatment decreased furin activity and cleavage. A post hoc analysis of a human clinical trial indicated that ergocalciferol treatment also reduced serum furin activity and iFGF23 cleavage. The findings reveal a direct mechanism by which vitamin D enhances iFGF23 bioactivity by post-transcriptional regulation via VDR-mediated suppression of furin.
