Project Details
Projekt
Molecular mechanisms of ferroportin-mediated protection against bone diseases
Applicants
Dr. Sandro Altamura; Professor Dr. Lorenz C. Hofbauer
Subject Area
Endocrinology, Diabetology, Metabolism
Term
since 2020
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 436298031
Balanced iron levels are essential for bone health, as both iron deficiency and iron overload disorders frequently lead to complications like osteopenia and osteoporosis. Systemic iron homeostasis is regulated by the hepcidin/ferroportin (FPN) system. FPN mediates iron release from specialized iron-exporting cells, such as duodenal enterocytes and splenic macrophages. Hepcidin, a hepatic peptide hormone, regulates FPN levels post-translationally by inducing its internalization and degradation, thus controlling the amount of iron exported. FPN is also expressed in cells that lack a well-recognized role in iron handling, where it is hypothesized to act as a "safety valve" to prevent excessive iron accumulation.During the first funding period, we investigated the role of FPN in bone cells. By utilizing the gain-of-function FPN p.C326S mutation, which makes FPN resistant to hepcidin binding, we developed conditional mouse models with osteoclast- or osteoblast-specific iron deficiency. Our results revealed that FPN stabilization in osteoclasts leads to intracellular iron deficiency and Hypoxia Inducible Factor 2α (HIF2α) activation, resulting in increased bone resorption and bone loss. In contrast, FPN stabilization in osteoblasts, leading to iron deficiency, caused impaired osteoblastogenesis and reduced mineralization. These findings highlight the crucial role of FPN in maintaining bone homeostasis and suggest that cell-autonomous iron deficiency may contribute to bone loss diseases via distinct mechanisms.In the second funding period, we will test the hypothesis that hypoxia and inflammatory signals converge to regulate bone FPN expression and bone iron content, thereby contributing to altered bone remodeling. Specifically, we aim to investigate the molecular up-stream mechanisms whereby hypoxia alters FPN regulation in bone cells and how inflammatory cytokines modulate iron levels in bone tissue. These insights could pave the way for new therapeutic approaches targeting iron homeostasis to prevent bone diseases.
DFG Programme
Research Units
