Vitamin D receptor-independent FGF23 actions in regulating phosphate and vitamin D metabolism

Abstract

FGF23 suppresses both serum phosphate and 1,25-dihydroxyvitamin D [1,25D] levels in vivo. Because 1,25D itself is a potent regulator of phosphate metabolism, it has remained unclear whether FGF23-induced changes in phosphate metabolism were caused by a 1,25D-independent mechanism. To address this issue, we intravenously administered recombinant FGF23 to vitamin D receptor (VDR) null (KO) mice as a rapid bolus injection and evaluated the early effects of FGF23. Administration of recombinant FGF23 further decreased the serum phosphate level in VDR KO mice, accompanied by a reduction in renal sodium-phosphate cotransporter type IIa (NaPi2a) protein abundance and a reduced renal 25-hydroxyvitamin D-1alpha-hydroxylase (1alphaOHase) mRNA level. Thus FGF23-induced changes in NaPi2a and 1alphaOHase expression are independent of the 1,25D/VDR system. However, 24-hydroxylase (24OHase) mRNA expression remained undetectable by the treatment with FGF23. We also analyzed the regulatory mechanism for FGF23 expression. The serum FGF23 level was almost undetectable in VDR KO mice, whereas dietary calcium supplementation significantly increased circulatory levels of FGF23 and its mRNA abundance in bone. This finding indicates that calcium is another determinant of FGF23 production that occurs independently of the VDR-mediated mechanism. In contrast, dietary phosphate supplementation failed to induce FGF23 expression in the absence of VDR, whereas marked elevation in circulatory FGF23 was observed in wild-type mice fed with a high-phosphate diet. Taken together, FGF23 works, at least in part, in a VDR-independent manner, and FGF23 production is also regulated by multiple mechanisms involving VDR-independent pathways.

Hyperphosphatemic familial tumoral calcinosis caused by a mutation in GALNT3 in a European kindred

“…However, the fact that mutations in GALNT3 and in FGF23 result in a similar phenotype (Topaz et al 2004;Benet-Page`s et al 2005), and the fact that FGF23 levels are perturbed in patients with ppGalNacT3 deficiency (Topaz et al 2004) indicate that the two proteins participate in a common regulatory pathway. FGF23 decreases circulating phosphate levels by downregulation of NaPiIIa (Shimada et al 2005), the major phosphate transporter in the renal proximal tubule, by inhibition of NaPiIIb, responsible for trans-intestinal phosphate transport , and by down-regulation of 1-alpha-hydroxylation of 25-hydroxycholecalciferol (Inoue et al 2005). Proteolytic degradation of FGF23 is believed to play a major role in regulating these activities (Saito et al 2003).…”

FGF-23: estado da arte

“…When those animals received a Ca-supplemented diet, a significant increase was observed in the expression of the messenger RNA of FGF-23 in bone tissue, thus indicating that Ca could be another determinant of FGF-23 production. 68 Recently, our group has studied 72 hemodialysis patients, in whom bone remodeling and the effects of Ca overload were assessed. At the beginning of the study, after a period without P binders and calcitriol, patients underwent bone biopsy, computed tomography of the coronary arteries for assessing Ca score, in addition to measuring biochemical markers of bone remodeling.…”

Enhanced FGF23 production in mice expressing PI3K‐insensitive GSK3 is normalized by β‐blocker treatment

“…Its main target is the kidney, where FGF23 inhibits tubular phosphate but fosters tubular calcium reabsorption (14)(15)(16)(17)(18)(19)(20)(21). Renal expression of FGF23 is observed in polycystic kidneys (22).…”