In Vivo Analyses of Fibroblast Growth Factor-23 Function

A major focus of our research is to determine the roles and interactions of key molecules controlling mineral homeostasis, particularly phosphate homeostasis. Phosphate is essential, not only for signaling and energy metabolism, but also for normal skeletal growth and development. Disturbances in phosphate homeostasis can affect the functional activities of almost any organ system.

Despite its wide biological importance and significance, the regulation of phosphate homeostasis is not yet clearly understood. Recent studies have identified a number of molecules that have phosphaturic activities, including fibroblast growth factor-23 (FGF-23, a circulating phosphaturic factor), frizzled-related protein 4 (FRP4), and the matrix extracellular phosphoglycoprotein (MEPE). Among these newly identified molecules, only FGF-23 has been implicated in various human diseases, including autosomal dominant hypophosphatemic rickets (ADHR), autosomal recessive hyposphosphatemic rickets (ARHR), X-linked hypophosphatemia (XLH), oncogenic osteomalacia (OOM), chronic kidney disease, and familial tumoral calcinosis (FTC).

We are using genetically altered mouse models to modulate FGF-23 actions in order to determine (1) the in vivo mechanism of abnormal phosphate homeostasis; (2) the in vivo effects of circulating Fgf-23; (3) the in vivo role of vitamin D in mediating Fgf-23 actions; (4) the consequence of hyperphosphatemia on cell death and tissue atrophy; and (5) the function of Fgf-23 as an inhibitor of mineralization in vitro. We are also investigating possible autocrine functions of FGF-23 on skeletal mineralization and bone cell differentiation in vitro, and are examining interactions between Fgf-23, klotho, and Wnt signaling. The lab is currently establishing new methods to manipulate the expression of various genes simultaneously in any specific tissue. These new methods will allow us to examine interactions among various molecules, and will help avoid systemic effects. Our research not only aims to improve our understanding of normal regulation of phosphate homeostasis, but also aims to designate selective interventions of disorders associated with abnormal phosphate homeostasis, including chronic renal diseases, XLH, ADHR, ARHR, FTC, diabetic ketoacidosis, and osteomalacia.