Iron deficiency drives an autosomal dominant hypophosphatemic rickets (ADHR) phenotype in fibroblast growth factor-23 (Fgf23) knock-in mice
Open Access
- 17 October 2011
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 108 (46), E1146-E1155
- https://doi.org/10.1073/pnas.1110905108
Abstract
Autosomal dominant hypophosphatemic rickets (ADHR) is unique among the disorders involving Fibroblast growth factor 23 (FGF23) because individuals with R176Q/W and R179Q/W mutations in the FGF23 176RXXR179/S180 proteolytic cleavage motif can cycle from unaffected status to delayed onset of disease. This onset may occur in physiological states associated with iron deficiency, including puberty and pregnancy. To test the role of iron status in development of the ADHR phenotype, WT and R176Q-Fgf23 knock-in (ADHR) mice were placed on control or low-iron diets. Both the WT and ADHR mice receiving low-iron diet had significantly elevated bone Fgf23 mRNA. WT mice on a low-iron diet maintained normal serum intact Fgf23 and phosphate metabolism, with elevated serum C-terminal Fgf23 fragments. In contrast, the ADHR mice on the low-iron diet had elevated intact and C-terminal Fgf23 with hypophosphatemic osteomalacia. We used in vitro iron chelation to isolate the effects of iron deficiency on Fgf23 expression. We found that iron chelation in vitro resulted in a significant increase in Fgf23 mRNA that was dependent upon Mapk. Thus, unlike other syndromes of elevated FGF23, our findings support the concept that late-onset ADHR is the product of gene–environment interactions whereby the combined presence of an Fgf23-stabilizing mutation and iron deficiency can lead to ADHR.Keywords
This publication has 50 references indexed in Scilit:
- Iron Modifies Plasma FGF23 Differently in Autosomal Dominant Hypophosphatemic Rickets and Healthy HumansJournal of Clinical Endocrinology & Metabolism, 2011
- Morphological Assessment of Basic Multicellular Unit Resorption Parameters in Dogs Shows Additional Mechanisms of Bisphosphonate Effects on BoneCalcified Tissue International, 2009
- Hypophosphatemia induced by intravenous administration of saccharated ferric oxide: Another form of FGF23-related hypophosphatemiaBone, 2009
- FGF23 Elevation and Hypophosphatemia after Intravenous Iron Polymaltose: A Prospective StudyJournal of Clinical Endocrinology & Metabolism, 2009
- Iron polymaltose-induced FGF23 elevation complicated by hypophosphataemic osteomalaciaAnnals of Clinical Biochemistry: International Journal of Laboratory Medicine, 2009
- Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs)JCI Insight, 2007
- Klotho converts canonical FGF receptor into a specific receptor for FGF23Nature, 2006
- Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolismNature Genetics, 2006
- FGF-23 Is a Potent Regulator of Vitamin D Metabolism and Phosphate HomeostasisJournal of Bone and Mineral Research, 2004
- Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT MethodMethods, 2001