title: Retinol deprivation partially rescues the skeletal mineralization defects of Phex-deficient Hyp mice.
abstract: X-linked hypophosphatemic rickets (XLH) is a genetic disorder caused by mutational inactivation of the PHEX gene, encoding a transmembrane endopeptidase expressed in osteoblasts. Since several experiments involving Phex-deficient Hyp mice have demonstrated that an increased expression of Fgf23 in osteoblasts is causative for the renal phosphate loss characteristic of XLH, we performed genome-wide expression analysis to compare differentiated osteoblasts from wildtype and Hyp mice. Here we did not only observe the expected increase of Fgf23 expression in the latter ones, but also a differential expression of genes that are either induced by or involved in retinoic acid signaling, which led us to analyze whether dietary retinol deprivation would influence the phenotype of Hyp mice. Unexpectedly, feeding a retinol-free diet resulted in a partial rescue of the growth plate and bone mineralization defects in 6 weeks old Hyp mice. When we fed the same diet for 24 weeks the amount of non-mineralized bone matrix (osteoid) was reduced by more than 70%, although phosphate homeostasis was unaffected. In contrast, a dietary normalization of serum phosphate levels in Hyp mice reduced the osteoid amount by less than 30%, thereby demonstrating a previously unknown impact of retinol on the cell-autonomous mineralization defect of Phex-deficient osteoblasts.
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg Eppendorf, Hamburg 20246, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Seitz
authors.forename: Carsten
authors.initials: C
authors.lastname: Rendenbach
authors.forename: Florian
authors.initials: F
authors.lastname: Barvencik
authors.forename: Thomas
authors.initials: T
authors.lastname: Streichert
authors.forename: Anke
authors.initials: A
authors.lastname: Jeschke
authors.forename: Jochen
authors.initials: J
authors.lastname: Schulze
authors.forename: Michael
authors.initials: M
authors.lastname: Amling
authors.forename: Thorsten
authors.initials: T
authors.lastname: Schinke
mesh_terms: D000818:Animals; D001483:Base Sequence; D002113:Calcification, Physiologic; D017931:DNA Primers; D004032:Diet; D053098:Familial Hypophosphatemic Rickets / Q000503:physiopathology*; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000235:genetics; D040181:Genetic Diseases, X-Linked; D051379:Mice; D053402:PHEX Phosphate Regulating Neutral Endopeptidase / Q000235:genetics*; D016133:Polymerase Chain Reaction; D014801:Vitamin A / Q000008:administration & dosage / Q000037:antagonists & inhibitors*
chemical_list: D017931:DNA Primers; C000717428:Fgf23 protein, mouse; D014801:Vitamin A; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D053402:PHEX Phosphate Regulating Neutral Endopeptidase; C506232:Phex protein, mouse