Fibroblast growth factor-23 (FGF-23) is a recently identified molecule, and implicated in the pathogenesis of various human diseases, including in X-linked hypophosphatemia (XLH), oncogenic osteomalacia (OOM), autosomal dominant hypophosphatemic rickets (ADHR), familial tumor calcinosis (FTC) and chronic renal diseases. FGF-23 is one of the most important and determinant factors in maintaining phosphate homeostasis, and skeletal mineralization. The long-term objective of this grant proposal is to determine in vivo function, and regulation of FGF-23 in physiological and pathophysiological conditions. As a preliminary step of obtaining such objectives, we have recently generated mice, in which the Fgf-23 gene has been successfully ablated by homologous recombination. These Fgf-23 null mice exhibit hyperphosphatemia, increased vitamin-D activities, excessive mineralization in bone, and abnormal calcifications in the soft tissues. In this grant application, we propose to analyze the effects and interrelationship of three essential components, phosphate, Fgf-23 and vitamin-D, using Fgf-23 null mice. To determine the in vivo roles and regulations of Fgf-23, we propose to define the role of sodium-phosphate co-transporters (NaPi) in abnormal phosphate homeostasis in Fgf-23 null mice by generating Fgf-23-/- / NaPi 2a-/- double mutant mice, as outlined in (Specific Aim 1A). Further studies are also proposed to determine the effects of lowering serum phosphate by nicotinamide in Fgf-23 null animals (Specific Aim 1B). We will also investigate whether circulating FGF-23, exclusively derived from ?1(l) collagen (2.3 kb promoter) expressing osteoblasts, is sufficient to rescue the abnormal systemic phenotype of Fgf-23 null animals. We, therefore, propose to generate a mouse model that is completely ablated for endogenous Fgf-23, but expresses FGF-23 in osteoblasts which is then released into circulation (Specific Aim 2). Furthermore, we proposed to study the role of vitamin D in Fgf-23 mediated functions, by generating and molecular characterization of Fgf-23/1a hydroxylase and Fgf-23/vitamin D receptor double mutant mice (Fgf-23-/-/1a(OH)ase-/-;Fgf-23-/- / /DR-/-) (Specific Aims 3A, 3B). In addition, we will examine the In vivo bioactivities of Fgf-23 in a normocalcemic/normophosphatemic microenvironment that are independent of vitamin D signaling (Specific Aim 3B). Finally, we propose to analyze the autocrine function of Fgf-23 in vitro using calvarial osteoblasts and explants and will investigate its role as an inhibitor of mineralization (Specific Aim 4). Successful completion of this proposed grant application would generate data that will form the basis to design strategies to manipulate abnormal phosphate homeostasis and defective skeletal mineralization in patients suffering from a wide range of diseases including rickets, XLH, ADHR, OOM, FTC, and chronic renal failure, using FGF-23 or its interacting molecules as a potential therapeutic tool.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK073944-04
Application #
7786959
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Malozowski, Saul N
Project Start
2007-04-20
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2012-03-31
Support Year
4
Fiscal Year
2010
Total Cost
$422,288
Indirect Cost
Name
Harvard University
Department
Dentistry
Type
Schools of Dentistry
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Yuan, Quan; Jiang, Yan; Zhao, Xuefeng et al. (2014) Increased osteopontin contributes to inhibition of bone mineralization in FGF23-deficient mice. J Bone Miner Res 29:693-704
Zou, Huawei; Zhao, Xuefeng; Sun, Ningyuan et al. (2013) Effect of chronic kidney disease on the healing of titanium implants. Bone 56:410-5
Olauson, Hannes; Lindberg, Karolina; Amin, Risul et al. (2013) Parathyroid-specific deletion of Klotho unravels a novel calcineurin-dependent FGF23 signaling pathway that regulates PTH secretion. PLoS Genet 9:e1003975
Andrukhova, Olena; Zeitz, Ute; Goetz, Regina et al. (2012) FGF23 acts directly on renal proximal tubules to induce phosphaturia through activation of the ERK1/2-SGK1 signaling pathway. Bone 51:621-8
Yuan, Quan; Sato, Tadatoshi; Densmore, Michael et al. (2012) Deletion of PTH rescues skeletal abnormalities and high osteopontin levels in Klotho-/- mice. PLoS Genet 8:e1002726
Streicher, Carmen; Zeitz, Ute; Andrukhova, Olena et al. (2012) Long-term Fgf23 deficiency does not influence aging, glucose homeostasis, or fat metabolism in mice with a nonfunctioning vitamin D receptor. Endocrinology 153:1795-805
Yuan, Quan; Sato, Tadatoshi; Densmore, Michael et al. (2011) FGF-23/Klotho signaling is not essential for the phosphaturic and anabolic functions of PTH. J Bone Miner Res 26:2026-35
Yuan, Quan; Sitara, Despina; Sato, Tadatoshi et al. (2011) PTH ablation ameliorates the anomalies of Fgf23-deficient mice by suppressing the elevated vitamin D and calcium levels. Endocrinology 152:4053-61
Christov, Marta; Koren, Shany; Yuan, Quan et al. (2011) Genetic ablation of sfrp4 in mice does not affect serum phosphate homeostasis. Endocrinology 152:2031-6
Chu, E Y; Fong, H; Blethen, F A et al. (2010) Ablation of systemic phosphate-regulating gene fibroblast growth factor 23 (Fgf23) compromises the dentoalveolar complex. Anat Rec (Hoboken) 293:1214-26

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