CD Laboratory for Iron and Phosphate Biology

Iron and phosphate biology are linked via the peptide hormone FGF23. The administration of certain iron supplements leads to an undesirable reduction in phosphate levels. Research into the exact mechanism by the CD Laboratory could provide a remedy.

The homeostatic control of the concentration of phosphate in the plasma is mediated by the peptide hormone fibroblast growth factor-23 (FGF23) produced in the bone. An increase in the concentration of phosphate in the plasma leads to an increase in FGF23 and thus to increased excretion of phosphate via the urine.

Iron deficiency, the most common cause of anaemia in Central and Western Europe, also increases the formation of FGF23. However, this is cleaved in iron deficiency before it can be released from the osteocytes. Iron deficiency anaemia is often treated with intravenous (IV) iron. As a side effect, some iron preparations prevent the cleavage of FGF23 in the osteocytes, as a result of which it enters the plasma and - as described above - lowers the phosphate level. Such transient hypophosphataemia occurs in well over 50% of patients receiving intravenous iron.

Clinical signs of hypophosphataemia are typically proximal muscle weakness and bone degeneration. Repeated dosing of i.v. iron supplements can therefore lead to musculoskeletal complications including respiratory failure and bone fractures. The risk of hypophosphataemia following certain iron supplements appears to be mainly determined by the biophysical properties of the specific drug.

This adverse drug-induced FGF23 elevation is not only an unsolved medical problem, but also opens a window to a deeper understanding of the functional link between iron and phosphate homeostasis in humans. Elucidating the biological properties of FGF23 in the context of iron deficiency and i.v. iron therapy will lead to a better understanding of phosphate homeostasis and iron biology as a whole.

This CD Laboratory conducts detailed molecular studies aimed at understanding the transcriptional control, cleavage and receptor binding of FGF23, enabling not only safer clinical use of i.v. iron supplements and safer molecular drug development, but also new insights into iron and phosphate biology. The research also includes retrospective clinical studies targeting the role of acute hypophosphataemia as a perioperative and perinatal risk factor.

The physiological link between iron deficiency, treatment with i.v. iron supplements and phosphate homeostasis through FGF23 is only incompletely understood. The proposed work aims to elucidate unknown biological links and provides the basis for new insights into iron and phosphate biology with the perspective to fully understand FGF23 regulation, cleavage and receptor binding in the context of iron deficiency and open up potential novel drug targets for rare metabolic diseases, bone health and bone metastases.