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This version published online on February 26, 2004
Endocrinology, doi:10.1210/en.2003-1768
A more recent version of this article appeared on July 1, 2004
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Submitted on December 31, 2003
Accepted on February 18, 2004

Transgenic mice expressing Fibroblast Growth Factor 23 under the control of the {alpha}1(I) collagen promoter exhibit growth retardation, osteomalacia and disturbed phosphate homeostasis

Tobias Larsson, Richard Marsell, Ernestina Schipani, Claes Ohlsson, Östen Ljunggren, Harriet S Tenenhouse, Harald Jüppner, and Kenneth B Jonsson*

Department of Surgical Sciences, Uppsala University Hospital, SE-751 85 Uppsala, Sweden; Department of Medical Sciences, Uppsala University Hospital, SE-751 85 Uppsala, Sweden; Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA; Division of Endocrinology, Department of Internal Medicine, Sahlgrenska University Hospital, SE-413 45 Gothenburg, Sweden; Departments of Pediatrics and Human Genetics, McGill University, and The McGill University-Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada H3Z 2Z3

* To whom correspondence should be addressed. E-mail: Kenneth.Jonsson{at}surgsci.uu.se.

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 human wild-type FGF-23, under the control of the {alpha}1(I) collagen promoter, in cells of the osteoblastic lineage. At 8 weeks 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 hFGF-23 (undetectable in wild-type mice) was markedly elevated in transgenic mice (>7800 RU/ml). Serum PTH levels were increased in transgenic mice (231 ± 62 vs. 139 ± 44 ng/liter) 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 were significantly decreased in the kidneys of transgenic mice. Histology of tibiae displayed a disorganized and widened growth plate and pQCT 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.
Key words: 1{alpha}-hydroxylase • 24-hydroxylase • sodium/phosphate cotransporter • kidney • renal phosphate reabsorption




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