Recent studies have shown crucial roles of fibroblast growth factor-23 (FGF-23) and klotho in regulating calcium and phosphate homeostasis. FGF-23 is an important in vivo regulator of phosphate homeostasis, while klotho is involved in regulating calcium homeostasis by interacting with the epithelial calcium channel transient receptor potential-vanilloid-5 (TRPV5). Interestingly, Fgf-23 and klotho ablated (kl/kl, klotho-/-) mice have very similar physical, biochemical and morphological phenotypes;in vivo genetic manipulation of Fgf- 23 and klotho resulted in altered mineral ion homeostasis in these mutant mice. It is, however, not yet known how FGF-23, klotho and vitamin-D coordinately regulate mineral ion homeostasis. In this grant application we plan to use Fgf-23-/- , Fgf-23-/-1 a-hydroxylase mutant mice, and klotho-ablated and transgenic (Tg) mice as in vivo model systems to study possible in vivo interactions of these molecules, and their coordinated effects on mineral ion homeostasis. We propose to examine the effects of exogenous and endogenous FGF-23 on the induction of klotho in Fgf-23V and Fgf-23 -/-1 a-hydroxylase mice, and whether such interaction is a vitamin-D dependent process (Specific Aims 1 and 2). Our preliminary results suggest an in vivo interaction of FGF-23 and klotho. Furthermore, we found decreased renal expression of klotho in Fgf-23 mice;whether such decreased expression of klotho is partly responsible for premature aging-like features, and abnormal mineral ion homeostasis in Fgf-23 mice is not known. Therefore, we will determine the effects of restoration of klotho levels in Fgf-23-/- mice by generating Fgf-23-/-klotho-Tg mutant mice (Specific Aim 3). Finally to determine klotho -dependent and -independent functions of FGF-23, we would like to study Fgf- 23 -/-/klotho-/- mice, and Fgf-23 transgenic/klotho-/- mice. The long-term objective of this grant proposal is to determine in vivo function, and regulation of FGF-23, and klotho in physiological and pathological conditions. As a preliminary step of obtaining such objectives, we have recently generated and partially characterized both Fgf-23-/- , and Fgf-23 -/-1 a-hydroxylase double mutant mice. To study the effects of circulating FGF-23 on the induction of klotho to rescue the abnormal phenotypes of Fgf-23-/- , we generated another mouse model that is completely ablated for endogenous Fgf-23, but expresses FGF-23 in osteoblasts which is then released into circulation (Fgf-23-/-/Col1-FGF-23Tg mice). We will analyze the interrelationship of FGF-23, klotho and vitamin-D, and their effects on essential renal calcium and phosphate regulating molecules, including TRPV5, NaPi2a, Calbindin28k, NCX1, and PMCAbl and their effect on skeletogenesis. Successful completion of this proposed grant application would generate data that will form the basis to design strategies to manipulate abnormal mineral ion homeostasis and defective skeletal mineralization in wide range of diseases including rickets/osteomalacia, tumoral calcinosis and chronic renal failure, by developing novel therapies and fine tuning of the existing therapeutic modalities

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK077276-04
Application #
7872796
Study Section
Cellular and Molecular Biology of the Kidney Study Section (CMBK)
Program Officer
Kimmel, Paul
Project Start
2007-07-15
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
4
Fiscal Year
2010
Total Cost
$290,328
Indirect Cost
Name
Harvard University
Department
Dentistry
Type
Schools of Dentistry
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Ohnishi, Mutsuko; Razzaque, Mohammed S (2013) Osteo-renal cross-talk and phosphate metabolism by the FGF23-Klotho system. Contrib Nephrol 180:1-13
Uchihashi, Kazuyoshi; Nakatani, Teruyo; Goetz, Regina et al. (2013) FGF23-induced hypophosphatemia persists in Hyp mice deficient in the WNT coreceptor Lrp6. Contrib Nephrol 180:124-37
Razzaque, Mohammed S (2013) Phosphate toxicity and vascular mineralization. Contrib Nephrol 180:74-85
Hartman, Mor-Li; Groppo, Francisco; Ohnishi, Mutsuko et al. (2013) Can salivary phosphate levels be an early biomarker to monitor the evolvement of obesity? Contrib Nephrol 180:138-48
Osuka, Satoko; Razzaque, Mohammed S (2012) Can features of phosphate toxicity appear in normophosphatemia? J Bone Miner Metab 30:10-8
Goetz, Regina; Ohnishi, Mutsuko; Ding, Xunshan et al. (2012) Klotho coreceptors inhibit signaling by paracrine fibroblast growth factor 8 subfamily ligands. Mol Cell Biol 32:1944-54
Razzaque, M Shawkat (2012) The role of Klotho in energy metabolism. Nat Rev Endocrinol 8:579-87
Goetz, Regina; Ohnishi, Mutsuko; Kir, Serkan et al. (2012) Conversion of a paracrine fibroblast growth factor into an endocrine fibroblast growth factor. J Biol Chem 287:29134-46
Razzaque, M Shawkat (2011) Phosphate toxicity: new insights into an old problem. Clin Sci (Lond) 120:91-7
Ohnishi, Mutsuko; Kato, Shigeko; Akiyoshi, Junko et al. (2011) Dietary and genetic evidence for enhancing glucose metabolism and reducing obesity by inhibiting klotho functions. FASEB J 25:2031-9

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