Project Details
Projekt
Role of iron in bone metabolism of Hfe-hemochromatosis
Applicant
Professorin Maja Vujic Spasic, Ph.D.
Subject Area
Endocrinology, Diabetology, Metabolism
Term
since 2020
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 436298031
One of the most common forms of genetic iron overload disorders (hereditary hemochromatosis, HH) in Caucasians is caused by mutations in the HFE gene. Most of the HFE-HH cases are explained by attenuated BMP/SMAD signaling activity in hepatocytes and subsequently low expression of the liver hormone hepcidin. Given that there is no active mechanism to excrete the excess of iron, progressive iron accumulation in various tissues occurs, causing multiple organ dysfunction and eventually failure, including liver cirrhosis, hepatocellular carcinoma, cardiomyopathies, diabetes, and hypogonadism. Clinical observations have raised attention to the possible correlation between iron overload and the development of osteoporosis in HH. However, some inconsistencies between the data exist as to whether iron per se affects bone integrity in HFE-HH patients. We hypothesize that osteoporosis in HFE-HH does not primarily arise from iron overload, as our most recent work showed that systemic iron overload, at the degree present in Hfe-/- mice, does not associate with microarchitectural impairment of bones, thus excluding a negative effect of iron overload on bone integrity. We suggest that potential triggers throughout the course of disease progression could induce malfunction in bones. A more simple explanation would be gonadal deficiency, a commonly known cause of bone loss, due to its co-occurrence with iron overload in HFE-HH. Whether iron overload in Hfe-/- mice may act as additional culprit when other osteoporosis triggers are present, such as liver cirrhosis and endocrine defects, is currently unknown and will be investigated here. We believe that our findings will be of utmost relevance for the clinical care of HFE-HH patients and will aid in targeting the mechanisms of bone loss during iron overload pathology in HFE-HH.
DFG Programme
Research Units
