Novel Control of FGF23 in Metabolic Bone Disease

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Project Summary/Abstract: We identified Fibroblast growth factor-23 (FGF23) in a positional cloning approach to isolate the gene for autosomal dominant hypophosphatemic rickets (ADHR), characterized by hypophosphatemia secondary to renal phosphate wasting, rickets/osteomalacia and fracture. We made key mechanistic connections regarding the regulation of FGF23 expression by crossover iron and phosphate metabolism, showing that anemia caused late-onset ADHR in a mouse knock-in model of this disease. These findings significantly modify the current endocrine feedback paradigms, determining that biological stimuli outside of the known effectors of FGF23 control, namely anemia, could drive FGF23 production. Therefore, the molecular mechanisms by which FGF23 is regulated and controls phosphate handling are incompletely understood. This work is relevant to chronic kidney disease-mineral bone disorder (CKD- MBD), the largest patient population with co-disturbances in phosphate handling (markedly increased FGF23 leading to metabolic bone disease) and iron metabolism (progressive anemia as the kidneys fail) leading to increased fracture risk and mortality. Our novel preliminary data now make a link between these metabolic systems by demonstrating that erythropoietin (EPO) delivery, a cornerstone therapy for anemia in CKD-MBD, markedly elevated bone Fgf23 mRNA and circulating FGF23 protein in mice. Further, these increases occur by over-riding mechanisms that typically inhibit FGF23 production. Using a recently developed mouse model carrying conditional flox-Fgf23 alleles, our initial findings also support that EPO control of FGF23 may occur in bone cells outside of the ‘traditional’ expression sites of osteoblasts/osteocytes, thus potentially revealing novel regulatory systems for phosphate metabolism. In light of these new results, the molecular mechanisms dictating EPO-mediated FGF23 regulation during kidney disease onset and progression, remain to be defined. The central hypothesis for this proposal is: FGF23 is stimulated by EPO in osteoblasts/osteocytes and in hematopoietic progenitor cells leading to altered mineral metabolism. This axis may be a modifiable risk factor in CKD-MBD, therefore we expect our fundamental biological discoveries to provide novel translational insight into rare and common syndromes of altered FGF23 expression, and into the basic biology of phosphate metabolism.