Inactivation of klotho function induces hyperphosphatemia even in presence of high serum fibroblast growth factor 23 levels in a genetically engineered hypophosphatemic ( Hyp ) mouse model
Open Access
- 7 July 2009
- journal article
- research article
- Published by Wiley in The FASEB Journal
- Vol. 23 (11), 3702-3711
- https://doi.org/10.1096/fj.08-123992
Abstract
Hyp mice possess a mutation that inactivates the phosphate‐regulating gene, which is ho‐mologous to the endopeptidases of the X‐chromo‐some (PHEX). The mutation is associated with severe hypophosphatemia due to excessive urinary phosphate wasting. Such urinary phosphate wasting in Hyp mice is associated with an increased serum accumulation of fibroblast growth factor (FGF) 23. We wanted to determine the biological significance of increased serum FGF23 levels and concomitant hy‐pophosphatemia in Hyp mice and to evaluate whether FGF23 activity could be modified by manipulating klotho (a cofactor of FGF23 signaling). We generated Hyp and klotho double‐mutant mice (Hyp/klotho−/−). Severe hypophosphatemia of Hyp mice was reversed to hyperphosphatemia in Hyp/klotho−/− double mutants, despite the fact that the double mutants showed significantly increased serum levels of FGF23. Hyperphosphatemia in Hyp/klotho−/− mice was associated with increased renal expression of sodium/phosphate cotransporter 2a (NaPi2a) protein. Exogenous injection of bioactive parathyroid hormone 1‐34 down‐regulated renal expression of NaPi2a and consequently reduced serum levels of phosphate in Hyp/klotho−/− mice. Moreover, in con‐trast to the Hyp mice, the Hyp/klotho−/− mice showed significantly higher serum levels of 1,25‐dihydroxyvitamin D and developed extensive calcification in soft tissues and vascular walls. Furthermore, compared with the Hyp mice, Hyp/klotho−/− mice were smaller in size, showed features of generalized tissue atrophy, and generally died by 15‐20 wk of age. Our in vivo studies provide genetic evidence for a pathological role of increased FGF23 activities in regulating abnormal phosphate homeostasis in Hyp mice. Moreover, these results suggest that even when serum levels of FGF23 are significantly high, in the absence of klotho, FGF23 is unable to regulate systemic phosphate homeostasis. Our in vivo observations have significant clinical implications in dis‐eases associated with increased FGF23 activity and suggest that the functions of FGF23 can be therapeu‐tically modulated by manipulating the effects of klotho.—Nakatani, Y., Ohnishi, M., Razzaque, M. S. Inactivation of klotho function induces hyperphosphatemia even in presence of high serum fibroblast growth factor 23 levels in a genetically engineered hypophosphatemic (Hyp) mouse model. FASEBJ. 23, 3702‐3711 (2009). www.fasebj.orgFunding Information
- National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK077276)
This publication has 46 references indexed in Scilit:
- Reversal of mineral ion homeostasis and soft-tissue calcification of klotho knockout mice by deletion of vitamin D 1α-hydroxylaseKidney International, 2009
- Aberrant Phex function in osteoblasts and osteocytes alone underlies murine X-linked hypophosphatemiaJCI Insight, 2008
- Physiological Regulation and Disorders of Phosphate Metabolism -Pivotal Role of Fibroblast Growth Factor 23-Internal Medicine, 2008
- Can fibroblast growth factor 23 fine-tune therapies for diseases of abnormal mineral ion metabolism?Nature Clinical Practice Endocrinology & Metabolism, 2007
- Early Lethality inHypMice with Targeted Deletion ofPthGeneEndocrinology, 2007
- A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosisJCI Insight, 2007
- New Aspect of Renal Phosphate Reabsorption: The Type IIc Sodium-Dependent Phosphate TransporterAmerican Journal of Nephrology, 2007
- The emerging role of the fibroblast growth factor-23–klotho axis in renal regulation of phosphate homeostasisJournal of Endocrinology, 2007
- Premature aging in klotho mutant mice: Cause or consequence?Ageing Research Reviews, 2007
- Correlation between hyperphosphatemia and type II Na-Pi cotransporter activity in klotho miceAmerican Journal of Physiology-Renal Physiology, 2007