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Gene Expression Analysis of Kidneys From Transgenic Mice Expressing Fibroblast Growth Factor-23
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
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 Medical Sciences.
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2008 (English)In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 23, no 3, 827-833 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Fibroblast growth factor-23 (FGF23), a circulating protein produced in bone, causes decreased renal inorganic phosphate (Pi) reabsorption by reducing the expression of the sodium phosphate cotransporter type 2a (Npt2a). We have previously generated transgenic mice expressing human wild-type (WT) FGF23 under the control of the alpha1 (I) collagen promoter. METHODS: In this study, we performed a large-scale gene expression study of kidneys from FGF23 transgenic mice and WT littermates. Microarray expression data of key transcripts were verified by real-time RT-PCR analysis. RESULTS: Several genes that play a role in Pi regulation revealed decreased expression levels in the transgenic mice, such as Npt2a and Pdzk1, a scaffolding protein known to interact with Npt2a. Importantly, Klotho, a suggested FGF23 receptor cofactor, was the most significantly decreased transcript and alpha2-Na(+)/K(+)-ATPase (Atp1a2), a gene isoform of alpha1-Na(+)/K(+)-ATPase (Atp1a1) which has recently been shown to interact with Klotho and regulate calcium metabolism, was the most increased transcript. In contrast, other genes proposed to regulate Pi levels, such as secreted frizzled-related protein-4 (sFrp4) and Na(+)/H(+) exchanger regulatory factor-1 (Nherf1) revealed no changes. CONCLUSIONS: FGF23 transgenic mice display differentially expressed transcript levels of several genes essential in renal Pi regulation. These findings may lead to further understanding of how FGF23 mediates its actions on renal Pi regulation.

Place, publisher, year, edition, pages
2008. Vol. 23, no 3, 827-833 p.
National Category
Medical and Health Sciences Surgery
URN: urn:nbn:se:uu:diva-14822DOI: 10.1093/ndt/gfm672ISI: 000253858300010PubMedID: 17911089OAI: oai:DiVA.org:uu-14822DiVA: diva2:42593
Available from: 2008-05-30 Created: 2008-05-30 Last updated: 2013-12-05Bibliographically 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.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 333
Surgery, Fibroblast growth factor 23, FGF23, FGF-23, Phosphate homeostasis, Vitamin D, Klotho, Parathyroid hormone, PTH, Kirurgi
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
Available from: 2008-04-18 Created: 2008-04-18 Last updated: 2013-12-05Bibliographically approved

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Marsell, RichardKrajisnik, TijanaGöransson, HannaLjunggren, OstenJonsson, Kennet B
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Medical and Health SciencesSurgery

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