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Transgenic Mice Expressing Fibroblast Growth Factor 23 under the Control of the 1(I) Collagen Promoter Exhibit Growth Retardation, Osteomalacia, and Disturbed Phosphate Homeostasis

Department of Surgical Sciences (T.L., R.M., K.B.J.), Uppsala University Hospital, SE-751 85 Uppsala, Sweden; Department of Medical Sciences (T.L., O.L.), Uppsala University Hospital, SE-751 85 Uppsala, Sweden; Endocrine Unit (E.S., H.J.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114; Division of Endocrinology (C.O.), Department of Internal Medicine, Sahlgrenska University Hospital, SE-413 45 Gothenburg, Sweden; and Departments of Pediatrics and Human Genetics (H.S.T.), McGill University, and The McGill University-Montreal Children’s Hospital Research Institute, Montreal, Quebec, Canada H3Z 2Z3

Address all correspondence and requests for reprints to: Kenneth B. Jonsson, Department of Surgical Sciences, University Hospital, SE-751 85, Uppsala, Sweden. 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 wild-type human FGF-23, under the control of the 1(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.

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