Comparative pathophysiology of excessive Fgf23 secretion in Hyp and CKD mice

• Applicants: Professor Dr. Jan Baumbach; Professor Dr. Axel Karl Walch
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 565905120

Hypersecretion 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 murine homolog 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 better understand the regulation of FGF23 secretion and the pathophysiological sequelae of FGF23 excess. Our preliminary data from mouse CKD models have shown that excessive FGF23 may drive activation of pro-inflammatory pathways in the injured kidney. We will use a comparative approach in Hyp mice as a model of FGF23 excess with normal kidney function and in 5/6 nephrectomized CKD mice as a model of FGF23 excess in the setting of an injured kidney 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? The project uses a comparative, unbiased multi-omics approach in Hyp and CKD mice, harnessing the power of spatial transcriptomics and mass spectrometry imaging-based spatial metabolomics/proteomics on bone and kidney cryosections in combination with computational systems medicine. In both mouse models, we will modulate FGF23 secretion by dietary means, and FGF23 action by acute anti-FGF23 antibody-mediated inhibition. The innovativeness and relevance of the project are extremely high. The application of spatial genomics in bone cryosections to address FGF23 biology is ground-breaking and pioneering. In addition, there has never been a comprehensive and comparative integration of data at the genomic, transcriptomic, proteomic, and metabolomic level in kidneys of Hyp and CKD mice, coupled with acute inhibition of FGF23 signaling. We are positive that the project will lead to important discoveries with a major translational potential, and with major scientific and societal impact. Primary researchers involved. The project combines the expertise of Reinhold Erben in FGF23 biology with the expertise of Axel Walch in spatial metabolomics and the expertise of Jan Baumbach in computational systems medicine.

• DFG Programme: Research Grants
• International Connection: Austria
• Cooperation Partner: Professor Dr. Reinhold Erben