AbstractProper control of serum phosphate concentrations is required to maintain skeletal integrity. Wepreviously identified missense mutations in Fibroblast growth factor-23 (FGF23) as the cause ofautosomal dominant hypophosphatemic rickets (ADHR), characterized by hypophosphatemiasecondary to isolated renal phosphate wasting and metabolic bone disease. We subsequentlydemonstrated that inactivating FGF23 mutations result in the mirror-image disorder to ADHR,hyperphosphatemic familial tumoral calcinosis (hfTC), manifested by markedly elevated serumphosphate and often severe ectopic and vascular calcifications. Further, FGF23 is elevated in X-linkedhypophosphatemic rickets (XLH) and increased circulating FGF23 is also associated with a 5-6 foldhigher mortality risk in patients with chronic kidney disease-mineral bone disorder (CKD-MBD). Thereare currently no cures for the metabolic bone disease, only maintenance treatments, for theaforementioned syndromes. Although much progress has been made towards understanding bothbasic and clinical aspects of phosphate metabolism, the fundamental mechanisms regulating FGF23bioactivity under normal conditions and in disease are unknown. Certainly, the discovery of the FGF23co-receptor ?-Klotho (?KL) was a major step forward in our understanding of FGF23 actions in targettissues, however the downstream pathways directing phosphate metabolism in kidney, and thus overallbone health remain unclear. These exploratory studies are based upon initial, exciting findings derivedthrough an unbiased approach, and will test the hypothesis that specific intermediaries are upregulatedby FGF23 and control phosphate handling in situations of clamped serum FGF23 and in the absence of?KL-mediated signaling. The specific aims undertaken herein will examine pathways new to thephosphate field, thus having the potential to produce significant impact as a means to potentially controlphosphate handling in diseases of FGF23 excess or absence. A dovetailed combination of ex vivo andin vivo approaches will be undertaken to examine a novel functional FGF23 axis, and this proposal willalso explore direct inhibition of FGF23 bioactivity through previously unrecognized pathways in mousemodels of genetic hypophosphatemia. It is anticipated that successful completion of this work wouldprovide important targets for rare and common disorders of phosphate handling.
|Effective start/end date||7/1/16 → 6/30/18|
- National Institutes of Health: $173,250.00