Bone-Kidney Axis

Enhanced secretion of the bone-derived hormone fibroblast growth factor-23 (FGF23) is a hallmark not only of renal phosphate-wasting diseases such as X-linked hypophosphatemia (XLH) but also of chronic kidney disease (CKD). Although the mechanisms driving FGF23 secretion are controversial, there is solid evidence that FGF23 blood levels are an independent predictor of disease progression and overall mortality in CKD. An important question in this context is why? XLH is the most frequent inherited renal phosphate-wasting disease in humans. The mouse model of this disease is Hyp (hypophosphatemia). XLH patients and Hyp mice are characterized by loss-of-function mutations in PHEX (Phosphate-regulating endopeptidase homolog, X-linked). The mechanisms by which PHEX mutations lead to excessive secretion of FGF23 are poorly understood. Here, we plan to leverage Hyp and CKD mice in a comparative approach to tackle two key questions: (i) What is driving increased bony FGF23 secretion in Hyp and CKD mice? and (ii) What are the mechanisms driving maladaptive FGF23 signaling in the injured kidney of CKD mice? To address these questions, we will harness the power of newly developed multi-omics spatial biology techniques in combination with computational systems medicine. The project will lead to important new insight into the regulation of FGF23 secretion and the pathophysiological sequelae of FGF23 excess, and may ultimately improve the therapy of XLH and CKD patients.