Genetic evidence of serum phosphate-independent functions of FGF-23 on bone.
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 regula...
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Public Library of Science (PLoS)
2008-08-01
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| Series: | PLoS Genetics |
| Online Access: | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1000154&type=printable |
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| author | Despina Sitara Somi Kim Mohammed S Razzaque Clemens Bergwitz Takashi Taguchi Christiane Schüler Reinhold G Erben Beate Lanske |
| author_facet | Despina Sitara Somi Kim Mohammed S Razzaque Clemens Bergwitz Takashi Taguchi Christiane Schüler Reinhold G Erben Beate Lanske |
| author_sort | Despina Sitara |
| collection | DOAJ |
| description | 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-/-) 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-/- 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-/- mice on phosphate homeostasis and skeletal mineralization. Fgf-23-/-/NaPi2a-/- double mutant mice are viable and exhibit normal physical activities when compared to Fgf-23-/- animals. Biochemical analyses show that ablation of NaPi2a from Fgf-23-/- mice reversed hyperphosphatemia to hypophosphatemia by 6 weeks of age. Surprisingly, despite the complete reversal of serum phosphate levels in Fgf-23-/-/NaPi2a-/-, their skeletal phenotype still resembles the one of Fgf23-/- 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-/- 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. |
| format | Article |
| id | doaj-art-a9bc92bfb8a945738fef285986309caf |
| institution | OA Journals |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2008-08-01 |
| publisher | Public Library of Science (PLoS) |
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| spelling | doaj-art-a9bc92bfb8a945738fef285986309caf2025-08-20T02:17:24ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042008-08-0148e100015410.1371/journal.pgen.1000154Genetic evidence of serum phosphate-independent functions of FGF-23 on bone.Despina SitaraSomi KimMohammed S RazzaqueClemens BergwitzTakashi TaguchiChristiane SchülerReinhold G ErbenBeate LanskeMaintenance 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-/-) 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-/- 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-/- mice on phosphate homeostasis and skeletal mineralization. Fgf-23-/-/NaPi2a-/- double mutant mice are viable and exhibit normal physical activities when compared to Fgf-23-/- animals. Biochemical analyses show that ablation of NaPi2a from Fgf-23-/- mice reversed hyperphosphatemia to hypophosphatemia by 6 weeks of age. Surprisingly, despite the complete reversal of serum phosphate levels in Fgf-23-/-/NaPi2a-/-, their skeletal phenotype still resembles the one of Fgf23-/- 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-/- 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.https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1000154&type=printable |
| spellingShingle | Despina Sitara Somi Kim Mohammed S Razzaque Clemens Bergwitz Takashi Taguchi Christiane Schüler Reinhold G Erben Beate Lanske Genetic evidence of serum phosphate-independent functions of FGF-23 on bone. PLoS Genetics |
| title | Genetic evidence of serum phosphate-independent functions of FGF-23 on bone. |
| title_full | Genetic evidence of serum phosphate-independent functions of FGF-23 on bone. |
| title_fullStr | Genetic evidence of serum phosphate-independent functions of FGF-23 on bone. |
| title_full_unstemmed | Genetic evidence of serum phosphate-independent functions of FGF-23 on bone. |
| title_short | Genetic evidence of serum phosphate-independent functions of FGF-23 on bone. |
| title_sort | genetic evidence of serum phosphate independent functions of fgf 23 on bone |
| url | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1000154&type=printable |
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