FGF23-induced hypophosphatemia persists in Hyp mice deficient in the WNT coreceptor Lrp6.

Deregulated phosphate homeostasis can lead to a wide range of disorders, including myopathy, cardiac dysfunction, and skeletal abnormalities. Therefore, characterization of the molecular regulation of phosphate metabolism is of pathophysiological and clinical significance. Hyp mouse is the model for human X-linked hypophosphatemia which is due to mutations that inactivate the endopeptidases of the X chromosome (PHEX). PHEX inactivation leads to increased serum levels of fibroblast growth factor 23 (FGF23), a phosphaturic hormone that induces excessive renal phosphate excretion and severe hypophosphatemia. The expression of WNT signaling components is increased in Hyp mice. To determine the potential role of WNT signaling in FGF23-mediated hypophosphatemia, we cross-bred Hyp mice with mice deficient in the WNT coreceptor low-density lipoprotein receptor-related protein 6 (Lrp6) to generate Hyp and Lrp6 double mutant mice (Hyp/Lrp6). Like Hyp mice, Hyp/Lrp6 double mutants maintained high serum levels of FGF23, and accordingly exhibited hypophosphatemia to the same degree as the Hyp mice did, indicating that genetically reducing WNT signaling does not impact FGF23-induced phosphaturia. Moreover, similar to Hyp mice, the Hyp/Lrp6 double mutants also exhibited reduced mineralization of the bone, further supporting that reduced WNT signaling does not affect the chronic phosphate wasting caused by excess FGF23 in these mice. In further support of our finding, injection of bioactive FGF23 protein into Lrp6 mutant mice reduced serum phosphate levels to a similar degree as FGF23 injection into wild-type mice. Our in vivo studies provide genetic and pharmacological evidence for a WNT-independent function of FGF23 in the regulation of phosphate homeostasis.

Correlation between hyperphosphatemia and type II Na-Pi cotransporter activity in klotho mice.

Recent studies have demonstrated that klotho protein plays a role in calcium/phosphate homeostasis. The goal of the present study was to investigate the regulation of Na-P(i) cotransporters in klotho mutant (kl/kl) mice. The kl/kl mice displayed hyperphosphatemia, high plasma 1,25(OH)(2)D(3) levels, increased activity of the renal and intestinal sodium-dependent P(i) cotransporters, and increased levels of the type IIa, type IIb, and type IIc transporter proteins compared with wild-type mice. Interestingly, transcript levels of the type IIa/type IIc transporter mRNA abundance, but not transcripts levels of type IIb transporter mRNA, were markedly decreased in kl/kl mice compared with wild-type mice. Furthermore, plasma fibroblast growth factor 23 (FGF23) levels were 150-fold higher in kl/kl mice than in wild-type mice. Feeding of a low-P(i) diet induced the expression of klotho protein and decreased plasma FGF23 levels in kl/kl mice, whereas colchicine treatment experiments revealed evidence of abnormal membrane trafficking of the type IIa transporter in kl/kl mice. Finally, feeding of a low-P(i) diet resulted in increased type IIa Na-P(i) cotransporter protein in the apical membrane in the wild-type mice, but not in kl/kl mice. These results indicate that hyperphosphatemia in klotho mice is due to dysregulation of expression and trafficking of the renal type IIa/IIc transporters rather than to intestinal P(i) uptake.