Transgenic mice expressing fibroblast growth factor 23 under the control of the α1 (I) collagen promoter exhibit growth retardation, osteomalacia, and disturbed …

T Larsson, R Marsell, E Schipani, C Ohlsson… - …, 2004 - academic.oup.com
T Larsson, R Marsell, E Schipani, C Ohlsson, O Ljunggren, HS Tenenhouse, H Jüppner…
Endocrinology, 2004academic.oup.com
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 …
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 α1(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.
Oxford University Press