1,25-Dihydroxyvitamin D3 regulates furin-mediated FGF23 cleavage
Han Xie, Isinsu Bastepe, Wen Zhou, Birol Ay, Zara Ceraj, Ignacio A. Portales-Castillo, Eva S. Liu, Sherri-Ann M. Burnett-Bowie, Harald Jüppner, Eugene P. Rhee, Murat Bastepe, Petra Simic
Han Xie, Isinsu Bastepe, Wen Zhou, Birol Ay, Zara Ceraj, Ignacio A. Portales-Castillo, Eva S. Liu, Sherri-Ann M. Burnett-Bowie, Harald Jüppner, Eugene P. Rhee, Murat Bastepe, Petra Simic
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Research Article Endocrinology Nephrology

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

Abstract

Intact fibroblast growth factor 23 (iFGF23) is a phosphaturic hormone that is cleaved by furin into N-terminal and C-terminal fragments. Several studies have implicated vitamin D in regulating furin in infections. Thus, we investigated the effect of 1,25-dihydroxyvitamin D3 [1,25(OH)2D] and the vitamin D receptor (VDR) on furin-mediated iFGF23 cleavage. Mice lacking VDR (Vdr–/–) had a 25-fold increase in iFGF23 cleavage, with increased furin levels and activity compared with wild-type (WT) littermates. Inhibition of furin activity blocked the increase in iFGF23 cleavage in Vdr–/– animals and in a Vdr-knockdown osteocyte OCY454 cell line. Chromatin immunoprecipitation revealed VDR binding to DNA upstream of the Furin gene, with more transcription in the absence of VDR. In WT mice, furin inhibition reduced iFGF23 cleavage, increased iFGF23, and reduced serum phosphate levels. Similarly, 1,25(OH)2D reduced furin activity, decreased iFGF23 cleavage, and increased total FGF23. In a post hoc analysis of a randomized clinical trial, we found that ergocalciferol treatment, which increased serum 1,25(OH)2D, significantly decreased serum furin activity and iFGF23 cleavage, compared with placebo. Thus, 1,25(OH)2D inhibits iFGF23 cleavage via VDR-mediated suppression of Furin expression, thereby providing a mechanism by which vitamin D can augment phosphaturic iFGF23 levels.

Authors

Han Xie, Isinsu Bastepe, Wen Zhou, Birol Ay, Zara Ceraj, Ignacio A. Portales-Castillo, Eva S. Liu, Sherri-Ann M. Burnett-Bowie, Harald Jüppner, Eugene P. Rhee, Murat Bastepe, Petra Simic

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Figure 2

Vdr–/– mice have higher furin levels and activity than WT mice.

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Vdr–/– mice have higher furin levels and activity than WT mice. Vdr–/– ...
Vdr–/– mice have an increase in furin (A) protein (n = 6 per group) and activity in plasma than mice on rescue diet (B) and normal diet (n = 8 per group) (C). The effect of calcitriol treatment on furin activity in Vdr–/– (n = 5 per group) (D) and Cyp27b1–/– mice (n = 7–12 per group) (E). Furin mRNA in bone and bone marrow (n = 3–4 per group) (F) and furin protein in bone marrow (G). qRT-PCR was performed using Gapdh as the relative control, and data were subsequently normalized to the levels in WT. Tubulin was used as a loading control in Western blots. Data represent the mean ± SEM. Data represent the mean ± SEM. P values by 2-tailed Student’s t test (A–D and F) or 2-tailed Student’s t test with Bonferroni’s correction (E). BL, baseline; D, calcitriol; qRT, quantitative reverse transcription.