Project Details
Projekt
Coordination Funds
Applicant
Professorin Dr. Martina Rauner
Subject Area
Endocrinology, Diabetology, Metabolism
Term
since 2020
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 436298031
Disorders of iron and bone metabolism frequently co-exist. As such, osteoporosis is often detected in individuals with iron deficiency, but also in patients with iron overload. Therefore, balanced iron levels are indispensable for bone health. The FerrOs consortium has integrated researchers with specific expertise in iron disorders and bone metabolism to unravel the interactions of the liver-iron-bone-axis. By combining our complementary expertise and sharing our unique animal models and molecular tools, we have set out to address the following aims: i) determine how iron affects bone, ii) investigate mechanisms of iron sensing, and iii) elucidate whether identified targets may be suitable for the treatment of iron-related bone disorders. In the first funding period, we have established reliable mouse models of iron-driven bone loss and uncovered sex-specific differences. We have shown that osteoclasts are key drivers of iron-induced bone loss and that cell autonomous osteoclast iron deficiency is self-sufficient to alter bone homeostasis. Moreover, dysregulations of osteoblast metabolism such as increased glycolysis have been identified as potential mechanisms driving iron-induced suppression of osteoblast function. In terms of iron sensing, robust methods have been developed to assess the interactions of liver sinusoidal endothelial cells (LSECs) and hepatocytes, which have aided in the identification of hepatocyte-secreted candidates that mediate the iron-dependent regulation of BMP6 in LSECs. Moreover, a plasma proteomics pipeline was developed that allowed the identification of CCL3 and CD44 as potential targets driving iron-induced bone loss. In the second funding period, we will follow-up on these observations to mechanistically address in terms of iron sensing, which hepatocyte-secreted factors mediate the iron-induced expression of BMP6 expression in LSECs, how BMP receptors and hemochromatosis proteins interact to regulate hepcidin expression, and how inflammation affects these interactions. Moreover, a strong focus will be put on identifying how iron affects bone (cell) function and how cell metabolic disturbances induced by iron overload contribute to pathologies in liver, bone, and macrophages, and whether these metabolic pathways can be targeted for therapies to mitigate liver damage and bone loss in iron overload conditions. Further, we plan to continue our measures for scientific exchange, collaboration and communication, which has allowed us to network intensively, and train early career researchers and clinician-scientists. Overall, this coordinated approach will generate substantial synergies that will be essential to dissect mechanisms of liver-bone crosstalk in iron handling, provide novel insights into iron-related (bone) disorders, and pave the way for novel therapeutic concepts.
DFG Programme
Research Units
