Transgenic Mice Expressing Fibroblast Growth Factor 23 under the Control of the α1(I) Collagen Promoter Exhibit Growth Retardation, Osteomalacia, and Disturbed Phosphate Homeostasis

Abstract

Mutations in the fibroblast growth factor 23 gene, FGF23, cause autosomal dominant hypophosphatemic rickets (ADHR). The gene product, FGF-23, is produced by tumors from patients with oncogenic osteomalacia (OOM), circulates at increased levels in most patients with X-linked hypophosphatemia (XLH) and is phosphaturic when injected into rats or mice, suggesting involvement in the regulation of phosphate (Pi) homeostasis. To better define the precise role of FGF-23 in maintaining Pi balance and bone mineralization, we generated transgenic mice that express wild-type human FGF-23, under the control of the alpha1(I) collagen promoter, in cells of the osteoblastic lineage. At 8 wk of age, transgenic mice were smaller (body weight = 17.5 +/- 0.57 vs. 24.3 +/- 0.37 g), exhibited decreased serum Pi concentrations (1.91 +/- 0.27 vs. 2.75 +/- 0.22 mmol/liter) and increased urinary Pi excretion when compared with wild-type littermates. The serum concentrations of human FGF-23 (undetectable in wild-type mice) was markedly elevated in transgenic mice (>7800 reference units/ml). Serum PTH levels were increased in transgenic mice (231 +/- 62 vs. 139 +/- 44 pg/ml), whereas differences in calcium and 1,25-dihydroxyvitamin D were not apparent. Expression of Npt2a, the major renal Na(+)/Pi cotransporter, as well as Npt1 and Npt2c mRNAs, was significantly decreased in the kidneys of transgenic mice. Histology of tibiae displayed a disorganized and widened growth plate and peripheral quantitative computerized tomography analysis revealed reduced bone mineral density in transgenic mice. The data indicate that FGF-23 induces phenotypic changes in mice resembling those of patients with ADHR, OOM, and XLH and that FGF-23 is an important determinant of Pi homeostasis and bone mineralization.

Iron deficiency drives an autosomal dominant hypophosphatemic rickets (ADHR) phenotype in fibroblast growth factor-23 (Fgf23) knock-in mice

“…In line with the known in vivo effects of Fgf23, we detected a marked decrease of Npt2a in ADHR mice on the low-iron diet (Fig. 4A) (31), with suppressed Cyp27b1 and elevated Cyp24 (Fig. 4C) corresponding to the inappropriately low 1,25D (Fig.…”

“…Excess FGF23 is associated with hypophosphatemia in ADHR and other hypophosphatemic patients (11,(28)(29)(30) and in murine models (8,26,31). We detected a significant increase in serum intact Fgf23 in the ADHR mice receiving the low-iron diet at 6 wk and in a proportion of the ADHR mice at 8 wk.…”

Premature aging in klotho mutant mice: Cause or consequence?

“…Transgenic mice over-expressing FGF-23 exhibit hypophosphatemia, with no significant changes in serum levels of calcium (Bai et al, 2004;Larsson et al, 2004;Shimada et al, 2004b), while an opposing effect of high serum levels of phosphate, and increased vitamin D activities are documented in Fgf-23 null mice (Shimada et al, 2004a;Sitara et al, 2004). More importantly, the phenotype of Fgf-23 null animals mimics patients with familial tumoral calcinosis (FTC), an autosomal recessive disorder characterized by ectopic calcifications and elevated serum levels of phosphate due to inactivating mutations in the FGF-23 gene (Benet-Pages et al, 2005;Frishberg et al, 2006).…”

Fibroblast Growth Factor‐23 and Heart Failure With Reduced Versus Preserved Ejection Fraction: MESA

“…Fibroblast growth factor‐23 (FGF‐23), a hormone involved in phosphorus and vitamin D homeostasis,14, 15, 16 is linked to the development of HF and left ventricular hypertrophy (LVH) 17, 18. The administration of recombinant FGF‐23 promotes cardiomyocyte growth in animal models and higher circulating FGF‐23 concentrations are associated with HF and cardiovascular events in kidney disease and general populations 18.…”