Interaktion zwischen Fibroblast growth factor-23 und dem Vitamin-D-Hormon-System

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.