Research Projects in Medical Sciences

Pathophysiologic Regulation of FGF-23 in Phosphate Homeostasis: Role of Vitamin D

Faculty: Beate Lanske, PhD
Investigators: Quan Yuan, PhD, Research Fellow, Michael Densmore, Research Associate
Funder(s): NIH/National Institute of Diabetes and Digestive and Kidney Diseases

Fibroblast growth factor-23 (FGF-23) is a recently identified molecule, which is 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 study, we are analyzing 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 are defining the role of sodium-phosphate cotransporters (NaPi) in abnormal phosphate homeostasis in Fgf-23 null mice by generating Fgf-23-/- / NaPi 2a-/- double mutant mice.

In further studies we will determine the effects of lowering serum phosphate by nicotinamide in Fgf-23 null animals. 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 are therefore generating a mouse model that is completely ablated for endogenous Fgf-23, but expresses FGF-23 in osteoblasts, which is then released into circulation. Furthermore, we plan 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-/-). In addition, we will examine the in-vivo bioactivities of Fgf-23 in a normocalcemic/normophosphatemic microenvironment that are independent of vitamin D signaling. Finally, we will analyze the autocrine function of Fgf-23 in vitro using calvarial osteoblasts and explants and will investigate its role as an inhibitor of mineralization. Successful completion of this study will 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.