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The Role of Fibroblast Growth Factor 23 in Phosphate Homeostasis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
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. , p. 78
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1367
Keywords [en]
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
Keywords [sv]
Medicin
National Category
Dermatology and Venereal Diseases
Identifiers
URN: urn:nbn:se:uu:diva-4489ISBN: 91-554-6013-5 (print)OAI: oai:DiVA.org:uu-4489DiVA, id: diva2:164929
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
List of papers
1. Diagnosis of a patient with oncogenic osteomalacia using a phosphate uptake bioassay of serum and magnetic resonance imaging
Open this publication in new window or tab >>Diagnosis of a patient with oncogenic osteomalacia using a phosphate uptake bioassay of serum and magnetic resonance imaging
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2001 In: Eur J Endocrinol, ISSN 0804-4643, Vol. 4, no 145, p. 469-76Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-91993 (URN)
Available from: 2004-09-02 Created: 2004-09-02Bibliographically approved
2. Immunohistochemical detection of FGF-23 protein in tumors that cause oncogenic osteomalacia
Open this publication in new window or tab >>Immunohistochemical detection of FGF-23 protein in tumors that cause oncogenic osteomalacia
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2003 In: Eur J Endocrinol, ISSN 0804-4643, Vol. 2, no 148, p. 269-76Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-91994 (URN)
Available from: 2004-09-02 Created: 2004-09-02Bibliographically approved
3. Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia
Open this publication in new window or tab >>Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia
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2003 In: N Engl J Med, ISSN 0028-4793, Vol. 17, no 348, p. 1656-63Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-91995 (URN)
Available from: 2004-09-02 Created: 2004-09-02Bibliographically approved
4. Circulating concentration of FGF-23 increases as renal function declines in patients with chronic kidney disease, but does not change in response to variation in phosphate intake in healthy volunteers
Open this publication in new window or tab >>Circulating concentration of FGF-23 increases as renal function declines in patients with chronic kidney disease, but does not change in response to variation in phosphate intake in healthy volunteers
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2003 In: Kidney Int, ISSN 0085-2538, Vol. 6, no 64, p. 2272-9Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-91996 (URN)
Available from: 2004-09-02 Created: 2004-09-02Bibliographically approved
5. Transgenic mice expressing Fibroblast Growth Factor-23 under the control of the α1 (I) collagen promoter exhibit growth retardation, Osteomalacia and disturbed phosphate homeostasis
Open this publication in new window or tab >>Transgenic mice expressing Fibroblast Growth Factor-23 under the control of the α1 (I) collagen promoter exhibit growth retardation, Osteomalacia and disturbed phosphate homeostasis
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2004 (English)In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 145, no 7, p. 3087-3094Article 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.

National Category
Surgery
Identifiers
urn:nbn:se:uu:diva-97055 (URN)10.1210/en.2003-1768 (DOI)14988389 (PubMedID)
Available from: 2008-04-18 Created: 2008-04-18 Last updated: 2017-12-14Bibliographically approved

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