Logo Logo
Switch language to English
Lehnert, Martina (2007): Interaktion zwischen Fibroblast growth factor-23 und dem Vitamin-D-Hormon-System. Dissertation, LMU München: Tierärztliche Fakultät



Fibroblast growth factor-23 (FGF-23), a molecule that is mutated in patients with autosomal dominant hypophosphatemic rickets (ADHR), appears to be involved in the regulation of phosphate homeostasis. Although increased levels of circulating FGF-23 were detected in patients with different phosphate-wasting disorders, it is not yet clear whether FGF-23 is directly responsible for the abnormal regulation of mineral ion homeostasis and consequently bone development. To explore these questions further, we generated a mouse model in which the entire Fgf-23 gene was replaced with the lacZ gene. Fgf-23 null (Fgf-23-/-) mice showed signs of growth retardation, developed severe hyperphosphatemia with elevated serum 1,25(OH)2D3 levels, and died by 13 weeks of age. Hyperphosphatemia in Fgf-23-/- mice was accompanied by skeletal abnormalities, as demonstrated by histological, molecular, and morphometric analyses. Fgf-23-/- mice had decreased bone mineral density of the limbs due to an accumulation of unmineralized osteoid leading to marked limb deformities. Moreover, Fgf-23-/- mice showed excessive mineralization in soft tissues. To further expand our understanding regarding the role of Fgf-23 in phosphate homeostasis and skeletal mineralization, we crossed Fgf-23-/- animals with Hyp mice, the murine equivalent of XLH. Interestingly, Hyp males lacking both Fgf-23 alleles were indistinguishable from Fgf-23-/- mice, both in terms of serum phosphate levels and skeletal changes, suggesting that Fgf-23 is downstream of the phosphate regulating gene with homologies to endopeptidases on the X chromosome (Phex). To explore further the role of the vitamin D axis for FGF-23 signaling, we mated Fgf-23 deficient mice and vitamin D receptor (VDR) mutant mice with a non-functioning VDR. To prevent secondary hyperparathyroidism in VDR and compound mutant mice, all mice were kept on a rescue diet enriched with calcium, phosphorus, and lactose. In analogy to previous findings, Fgf-23-/- animals showed hypercalcemia, hyperphosphatemia, growth retardation, ectopic calcifications, severe osteoidosis, skin atrophy, and renal dysfunction. In addition, here we describe that Fgf-23-/- mice are hypoglycemic, and have profoundly increased peripheral insulin sensitivity and improved subcutaneous glucose tolerance, but normal renal expression of the aging suppressor gene Klotho. Although VDR and double mutants on the rescue diet still had moderately elevated parathyroid hormone serum levels and lower bone mineral 76 density compared to wild-type mice, double mutant mice had normal body weight, were normocalcemic and normophosphatemic, and ectopic calcifications as well as renal dysfunction were absent. Ablation of vitamin D signaling in compound mutants also normalized subcutaneous glucose tolerance tests and insulin secretory response. In conclusion, our results indicate that the alterations in mineral and carbohydrate metabolism present in Fgf-23-/- mice require an intact vitamin D signaling pathway.