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Transgenic mice expressing Fibroblast Growth Factor-23 under the control of the α1 (I) collagen promoter exhibit growth retardation, Osteomalacia and disturbed phosphate homeostasis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
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2004 (English)In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 145, no 7, 3087-3094 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2004. Vol. 145, no 7, 3087-3094 p.
National Category
Surgery
Identifiers
URN: urn:nbn:se:uu:diva-97055DOI: 10.1210/en.2003-1768PubMedID: 14988389OAI: oai:DiVA.org:uu-97055DiVA: diva2:171837
Available from: 2008-04-18 Created: 2008-04-18 Last updated: 2017-12-14Bibliographically approved
In thesis
1. FGF23 - a possible Phosphatonin
Open this publication in new window or tab >>FGF23 - a possible Phosphatonin
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Human physiology is dependent on an accurate phosphate (Pi) homeostasis. Defective Pi regulation causes hyper- or hypophosphatemia, which are associated with ectopic calcification or impaired bone mineralization, and a shortened life span. Current endocrine models of Pi homeostasis are incomplete. However, studies of acquired and hereditary disorders of Pi homeostasis have revealed new potential Pi regulating hormones, Phosphatonin(s). One of these is fibroblast growth factor-23 (FGF23). FGF23 is produced in bone and is secreted into the circulation. Mutations in FGF23 causes disturbed Pi regulation, without the appropriate counter-regulatory actions of parathyroid hormone or vitamin D. By the generation of FGF23 transgenic mice, which display phenotypic similarities to patients with hypophosphatemic disorders, we show that FGF23 exerts endocrine actions in the kidney and causes osteomalacia. Renal FGF23 actions severely decrease Pi reabsorption and expression of Klotho, a suggested age suppressor gene, known to be crucial in FGF23 receptor binding and activation. In bone, our transgenic model displays impaired osteoclast polarization, which should be detrimental to osteoclastic bone resorption in osteomalacia. However, in our model osteoclasts efficiently participate in bone matrix degradation. Furthermore, we investigated a large population-based cohort in order to elucidate the role of FGF23 in normal physiology. Importantly, we were able to demonstrate an association of FGF23 to parathyroid hormone, renal function and bone mineral density and we found a correlation of FGF23 to weight and body fat mass. The studies on which this thesis is based, demonstrate that FGF23 has phosphatonin-like properties and that the skeleton functions as an endocrine organ. In addition, the results indicate that FGF23 has a role in bone mineral and lipid metabolism, and that FGF23 is a possible diagnostic marker and therapeutic target for the future.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 72 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 333
Keyword
Surgery, Fibroblast growth factor 23, FGF23, FGF-23, Phosphate homeostasis, Vitamin D, Klotho, Parathyroid hormone, PTH, Kirurgi
Identifiers
urn:nbn:se:uu:diva-8649 (URN)978-91-554-7165-1 (ISBN)
Public defence
2008-05-09, Rosénsalen, Akademiska Sjukhuset (Barnsjukhuset), Ingång 95/96, Uppsala, 09:15
Opponent
Supervisors
Available from: 2008-04-18 Created: 2008-04-18 Last updated: 2013-12-05Bibliographically approved
2. The Role of Fibroblast Growth Factor 23 in Phosphate Homeostasis
Open this publication in new window or tab >>The Role of Fibroblast Growth Factor 23 in Phosphate Homeostasis
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The regulation of serum phosphate (Pi) concentrations is a complex process and our current models are far from complete. Due to major advancements in biotechnology and the development of more powerful research tools, recent advances in the field of genetics has led to the identification of several candidates for the long sought-after phosphatonin(s), or Pi regulating hormones. One of these candidates is fibroblast growth factor 23 (FGF-23) and this thesis is based upon studies of the role of FGF-23 in Pi homeostasis. We demonstrate that FGF-23 is a secreted protein which is highly expressed in tumors giving rise to oncogenic hypophosphatemic osteomalacia (OOM). Furthermore, we have developed a two-site enzyme-linked immunosorbent assay for the detection of circulating FGF-23 and established that FGF-23 is present in the circulation of healthy individuals. Also, FGF-23 serum levels are elevated in patients with disturbances in Pi homeostasis such as OOM, X-linked hypophosphatemic rickets (XLH) and chronic kidney disease and are likely to play an important role in the pathogenesis of these disorders. A transgenic mouse model that express human FGF-23 under the control of the α1(I) collagen promoter exhibit similar clinical and biochemical characteristics as do patients with OOM, XLH and autosomal dominant hypophosphatemic rickets indicating that FGF-23 is an important determinant of Pi homeostasis, vitamin D metabolism and bone mineralization.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2004. 78 p.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1367
Keyword
Medicine, Fibroblast Growth Factor 23, FGF-23, phosphate homeostasis, vitamin D metabolism, sodium/phosphate cotransporters, autosomal dominant hypophosphatemic rickets, ADHR, X-linked hypophosphatemic rickets, XLH, oncogenic osteomalacia, OOM, PHEX, Medicin
National Category
Dermatology and Venereal Diseases
Identifiers
urn:nbn:se:uu:diva-4489 (URN)91-554-6013-5 (ISBN)
Public defence
2004-09-25, Enghoffsalen, UAS, ingång 50, b.v, Uppsala, 13:15
Opponent
Supervisors
Available from: 2004-09-02 Created: 2004-09-02 Last updated: 2013-12-05Bibliographically approved

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Marsell, RichardLjunggren, ÖstenJonsson, Kenneth B

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