dc.contributor.author | Sitara, Despina | |
dc.contributor.author | Kim, Somi | |
dc.contributor.author | Razzaque, Mohammed Shawkat | |
dc.contributor.author | Bergwitz, Clemens | |
dc.contributor.author | Taguchi, Takashi | |
dc.contributor.author | Schüler, Christiane | |
dc.contributor.author | Erben, Reinhold G. | |
dc.contributor.author | Lanske, Beate Klara Maria | |
dc.date.accessioned | 2011-04-24T03:37:33Z | |
dc.date.issued | 2008 | |
dc.identifier.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. | en_US |
dc.identifier.issn | 1553-7390 | en_US |
dc.identifier.uri | http://nrs.harvard.edu/urn-3:HUL.InstRepos:4874831 | |
dc.description.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. | en_US |
dc.language.iso | en_US | en_US |
dc.publisher | Public Library of Science | en_US |
dc.relation.isversionof | doi:10.1371/journal.pgen.1000154 | en_US |
dc.relation.hasversion | http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2483943/pdf/ | en_US |
dash.license | LAA | |
dc.subject | aging | en_US |
dc.subject | diabetes and endocrinology | en_US |
dc.subject | bone and mineral metabolism | en_US |
dc.subject | endocrinology | en_US |
dc.subject | genetics and genomics | en_US |
dc.subject | animal genetics | en_US |
dc.subject | disease models | en_US |
dc.subject | genetics of disease | en_US |
dc.subject | medical genetics | en_US |
dc.subject | molecular biology | en_US |
dc.subject | nephrology | en_US |
dc.subject | mineral metabolism and the kidney | en_US |
dc.subject | renal physiology | en_US |
dc.subject | pathology | en_US |
dc.subject | pathophysiology | en_US |
dc.subject | physiology | en_US |
dc.subject | renal, fluid, and electrolyte physiology | en_US |
dc.subject | rheumatology | en_US |
dc.title | Genetic evidence of serum phosphate-independent functions of FGF-23 on bone | en_US |
dc.type | Journal Article | en_US |
dc.description.version | Version of Record | en_US |
dc.relation.journal | PLoS Genetics | en_US |
dash.depositing.author | Razzaque, Mohammed Shawkat | |
dc.date.available | 2011-04-24T03:37:33Z | |
dash.affiliation.other | HMS^Medicine-Massachusetts General Hospital | en_US |
dc.identifier.doi | 10.1371/journal.pgen.1000154 | * |
dash.contributor.affiliated | Kim, Somi | |
dash.contributor.affiliated | Razzaque, Mohammed | |
dash.contributor.affiliated | Mannstadt, Beate | |
dash.contributor.affiliated | Bergwitz, Clemens | |