Genetic evidence of serum phosphate-independent functions of FGF-23 on bone

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Genetic evidence of serum phosphate-independent functions of FGF-23 on bone

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Title: Genetic evidence of serum phosphate-independent functions of FGF-23 on bone
Author: Sitara, Despina; Taguchi, Takashi; Schüler, Christiane; Erben, Reinhold G.; Kim, Somi; Razzaque, Mohammed Shawkat; Bergwitz, Clemens; Lanske, Beate Klara Maria

Note: Order does not necessarily reflect citation order of authors.

Citation: Sitara, Despina, Somi Kim, Mohammed S. Razzaque, Clemens Bergwitz, Takashi Taguchi, Christiane Schüler, Reinhold G. Erben, and Beate Lanske. 2008. Genetic evidence of serum phosphate-independent functions of FGF-23 on bone. PLoS Genetics 4(8): e1000154.
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Abstract: Maintenance of physiologic phosphate balance is of crucial biological importance, as it is fundamental to cellular function, energy metabolism, and skeletal mineralization. Fibroblast growth factor-23 (FGF-23) is a master regulator of phosphate homeostasis, but the molecular mechanism of such regulation is not yet completely understood. Targeted disruption of the Fgf-23 gene in mice (Fgf-23[super]−/−) elicits hyperphosphatemia, and an increase in renal sodium/phosphate co-transporter 2a (NaPi2a) protein abundance. To elucidate the pathophysiological role of augmented renal proximal tubular expression of NaPi2a in Fgf-23[super]−/− mice and to examine serum phosphate–independent functions of Fgf23 in bone, we generated a new mouse line deficient in both Fgf-23 and NaPi2a genes, and determined the effect of genomic ablation of NaPi2a from Fgf-23[super]−/− mice on phosphate homeostasis and skeletal mineralization. Fgf-23[super]−/−/NaPi2a[super]−/− double mutant mice are viable and exhibit normal physical activities when compared to Fgf-23[super]−/− animals. Biochemical analyses show that ablation of NaPi2a from Fgf-23[super]−/− mice reversed hyperphosphatemia to hypophosphatemia by 6 weeks of age. Surprisingly, despite the complete reversal of serum phosphate levels in Fgf-23[super]−/−/NaPi2a[super]−/−, their skeletal phenotype still resembles the one of Fgf23[super]−/− animals. The results of this study provide the first genetic evidence of an in vivo pathologic role of NaPi2a in regulating abnormal phosphate homeostasis in Fgf-23[super]−/− mice by deletion of both NaPi2a and Fgf-23 genes in the same animal. The persistence of the skeletal anomalies in double mutants suggests that Fgf-23 affects bone mineralization independently of systemic phosphate homeostasis. Finally, our data support (1) that regulation of phosphate homeostasis is a systemic effect of Fgf-23, while (2) skeletal mineralization and chondrocyte differentiation appear to be effects of Fgf-23 that are independent of phosphate homeostasis.
Published Version: doi:10.1371/journal.pgen.1000154
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2483943/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:4874831

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