<p class="first" id="d1108247e135">Fibroblast growth factor-23 (FGF23) is a bone-derived
hormone regulating vitamin D
hormone production and renal handling of minerals by signaling through an FGF receptor/αKlotho
(Klotho) receptor complex. Whether Klotho has FGF23-independent effects on mineral
homeostasis is a controversial issue. Here, we aimed to shed more light on this controversy
by comparing male and female triple knockout mice with simultaneous deficiency in
Fgf23 and Klotho and a nonfunctioning vitamin D receptor (VDR) (Fgf23/Klotho/VDR)
with double (Fgf23/VDR, Klotho/VDR, and Fgf23/Klotho) and single Fgf23, Klotho, and
VDR mutants. As expected, 4-week-old Fgf23, Klotho, and Fgf23/Klotho knockout mice
were hypercalcemic and hyperphosphatemic, whereas VDR, Fgf23/VDR, and Klotho/VDR mice
on rescue diet were normocalcemic and normophosphatemic. Serum levels of calcium,
phosphate, and sodium did not differ between 4-week-old triple Fgf23/Klotho/VDR and
double Fgf23/VDR or Klotho/VDR knockout mice. Notably, 3-month-old Fgf23/Klotho/VDR
triple knockout mice were indistinguishable from double Fgf23/VDR and Klotho/VDR compound
mutants in terms of serum calcium, serum phosphate, serum sodium, and serum PTH, as
well as urinary calcium and sodium excretion. Protein expression analysis revealed
increased membrane abundance of sodium-phosphate co-transporter 2a (NaPi-2a), and
decreased expression of sodium-chloride co-transporter (NCC) and transient receptor
potential cation channel subfamily V member 5 (TRPV5) in Fgf23/Klotho/VDR, Fgf23/VDR,
and Klotho/VDR mice, relative to wild-type and VDR mice, but no differences between
triple and double knockouts. Further, ex vivo treatment of live kidney slices isolated
from wild-type and Klotho/VDR mice with soluble Klotho did not induce changes in intracellular
phosphate, calcium or sodium accumulation assessed by two-photon microscopy. In conclusion,
our data suggest that the main physiological function of Klotho for mineral homeostasis
in vivo is its role as co-receptor mediating Fgf23 action. © 2017 American Society
for Bone and Mineral Research.
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