title: FGF23-induced hypophosphatemia persists in Hyp mice deficient in the WNT coreceptor Lrp6.
abstract: 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.
authors: Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA 02115, USA.
authors: Kazuyoshi
authors: K
authors: Uchihashi
authors: Teruyo
authors: T
authors: Nakatani
authors: Regina
authors: R
authors: Goetz
authors: Moosa
authors: M
authors: Mohammadi
authors: Xi
authors: X
authors: He
authors: Mohammed S
authors: MS
authors: Razzaque
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D053098:Familial Hypophosphatemic Rickets / Q000000981:diagnostic imaging / Q000209:etiology / Q000235:genetics / Q000503:physiopathology*; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood / Q000502:physiology* / Q000633:toxicity; D006706:Homeostasis; D007015:Hypophosphatemia, Familial / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000172:deficiency* / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D053402:PHEX Phosphate Regulating Neutral Endopeptidase / Q000235:genetics / Q000502:physiology*; D010710:Phosphates / Q000378:metabolism; D011859:Radiography; D011994:Recombinant Proteins / Q000633:toxicity; D050610:Sodium-Phosphate Cotransporter Proteins, Type II / Q000096:biosynthesis / Q000235:genetics; D060449:Wnt Signaling Pathway
chemical_list: C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555476:Lrp6 protein, mouse; D010710:Phosphates; D011994:Recombinant Proteins; D050610:Sodium-Phosphate Cotransporter Proteins, Type II; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D053402:PHEX Phosphate Regulating Neutral Endopeptidase; C506232:Phex protein, mouse
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