Project Details
Projekt
Dissecting the bone cell-specific functions of ferroportin
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
Iron balance is critical for bone health, and osteoporosis represents a frequent complication of iron overload disorders. Systemic iron homeostasis is maintained via the hepcidin/ferroportin (Fpn) system. Fpn mediates the release of iron from iron-exporting cells such as duodenal enterocytes and splenic macrophages. Fpn levels, and thus the amount of iron exported, are post-translationally regulated by hepcidin, a hepatic hormone produced upon increased body iron levels that triggers Fpn internalization and degradation. Gain of function mutations of Fpn conferring resistance to hepcidin binding (FpnC326S) have been identified in patients with hereditary hemochromatosis type 4, characterized by an unrestricted systemic iron export that results in massive body iron overload. We have generated the FpnC326S knock-in mouse model of human hereditary hemochromatosis type 4. As in the human disease, this model displays systemic iron overload and massive iron deposition in parenchymal tissues, including the liver. By contrast, cell types expressing Fpn are iron depleted due to hepcidin resistance. The central aim of this project is to identify the mechanisms whereby cell autonomous alteration in osteoblast and osteoclast iron content may affect bone remodeling and impair bone quality. Using customized mouse models of Fpn ablation (Fpn-ko) or stabilization (FpnC326S) specifically in osteoblasts and osteoclasts, we will address the following aims: (I) How do cell-specific alterations in bone iron content affect bone remodeling under normal and estrogen-deficient conditions? (II) How does Fpn prevent iron-related toxicity of osteoclasts/osteoblasts and impaired bone quality? (III) Which molecular patterns link imbalanced osteoblast/osteoclast iron content to altered bone remodeling and what are the translational consequences? This approach will allow us dissecting the component of the hormonal impairment from the cell-autonomous bone iron status in the pathogenesis of bone disorders.
DFG Programme
Research Units
