Project Details
Projekt
Mechanisms of Tfr1-mediated iron uptake in bone and effects of iron on bone cell bioenergetics
Applicant
Professorin Dr. Martina Rauner
Subject Area
Endocrinology, Diabetology, Metabolism
Term
since 2020
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 436298031
Osteoblasts rely on a delicate balance of iron for proper differentiation and function. While iron is necessary for various cellular processes including DNA replication, proliferation, and cellular respiration, high levels of iron suppress osteoblast function. Despite this knowledge, our basic understanding on the impact of iron on osteoblasts remains very limited. To date, it is unclear how iron affects cellular functions in osteoblasts, what metabolic pathways are involved in regulating cell function, and if iron has the same impact depending on the differentiation state of the osteoblasts. It is even unknown how iron enters into osteoblasts. In this project, we will decipher these unresolved aspects. We hypothesize that transferrin receptor 1 (Tfr1) is the main iron-uptake receptor in osteoblasts. Moreover, our preliminary data lead us to hypothesize that high concentrations of iron promote osteoblast proliferation at the expense of differentiation, thereby limiting bone formation. These hypotheses will be tested by investigating the bone phenotype of osteoblast-specific Tfr1 knockout mice under homeostatic and hormone-deficiency conditions. As osteoclasts play a major role in bone resorption and the role of Tfr1 has also not been addressed in vivo, we will also characterize osteoclast-specific Tfr1 knock-out mice. To address how iron is utilized by specific osteoblast subsets, we will use single-cell RNA sequencing, untargeted metabolomics, and functional tests in vitro to link metabolic profiles to specific osteoblast subsets and their function (e.g. proliferation vs. matrix production vs. matrix mineralization). This project will unravel the importance of Tfr1 for iron uptake in the skeleton and will provide detailed insights into the role of iron in osteoblast function and bioenergetics.
DFG Programme
Research Units
