Molecular mechanisms of hypophosphatemia after intravenous iron therapy

Background Administration of the intravenous (IV) iron formulation ferric carboxymaltose (FCM) results in hypophosphatemia due to high FGF23 serum concentrations in the majority of treated patients with normal kidney function. We aim to identify the molecular mechanism causing hypophosphatemia after IV iron therapy.

Materials and methods FCM, ferric derisomaltose (FDI) and iron dextran (ID) were investigated in charge and phosphate-binding properties by isoelectric focusing, ion exchange chromatography and size exclusion chromatography (SEC). The impact of different IV iron formulations on DMP1 binding to its cell surface receptor αVβ3 integrin was assessed by ELISA and radio-ligand binding studies. DMP1-αVβ3 integrin signaling was investigated in osteoblastic precursor MC3T3-E1 cells with LC-MS/MS and western blotting.

Results At physiological pH, FCM was positively charged, while FDI and ID were negatively charged. When co-incubated with phosphate buffer only FCM changed its charge properties. High-affinity phosphate binding by FCM was confirmed by SEC followed by phosphate quantification. Phosphoproteomics analysis of MC3T3-E1 cell extracts revealed that treatment of cells with DMP1, a negative regulator of FGF23, causes activation of the integrin signaling pathway via the MAP kinases. FCM but neither FDI nor ID, strongly reduced DMP1 binding to αVβ3 integrin, as well as ERK phosphorylation as an indicator of activation of the MAP kinase activity.

Conclusions We demonstrate that FCM inhibits the DMP1 binding to αVβ3 integrin and thus the activation of the MAPK pathway in osteoblast precursor MC3T3-E1 cell line. This together with the high affinity of FCM to phosphate could be a possible explanation for FCM-induced hypophosphatemia.

 

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Publikationsverlauf

Artikel online veröffentlicht:
26. August 2022