Retinol deprivation partially rescues the skeletal mineralization defects of Phex-deficient Hyp mice.

TY - JOUR

T1 - Retinol deprivation partially rescues the skeletal mineralization defects of Phex-deficient Hyp mice.

AU - Seitz, Sebastian

AU - Rendenbach, Carsten

AU - Barvencik, Florian

AU - Streichert, Thomas

AU - Jeschke, Anke

AU - Schulze, Jochen

AU - Amling, Michael

AU - Schinke, Thorsten

N1 - Copyright © 2012 Elsevier Inc. All rights reserved.

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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.

KW - Animals

KW - Base Sequence

KW - Calcification, Physiologic

KW - DNA Primers

KW - Diet

KW - Familial Hypophosphatemic Rickets

KW - Fibroblast Growth Factors

KW - Genetic Diseases, X-Linked

KW - Mice

KW - PHEX Phosphate Regulating Neutral Endopeptidase

KW - Polymerase Chain Reaction

KW - Vitamin A

U2 - 10.1016/j.bone.2012.12.009

DO - 10.1016/j.bone.2012.12.009

M3 - SCORING: Journal article

C2 - 23266491

VL - 53

SP - 231

EP - 238

JO - BONE

JF - BONE

SN - 8756-3282

IS - 1

M1 - 1

ER -