Transferrin receptor 2 (Tfr2) is mainly expressed in the liver and controls iron homeostasis. Here, we identify Tfr2 as a regulator of bone homeostasis that inhibits bone formation. Mice lacking Tfr2 display increased bone mass and mineralization independent of iron homeostasis and hepatic Tfr2. Bone marrow transplantation experiments and studies of cell-specific Tfr2-knockout mice demonstrate that Tfr2 impairs BMP-p38MAPK signalling and decreases expression of the Wnt inhibitor sclerostin, specifically in osteoblasts. Reactivation of MAPK or overexpression of sclerostin rescues skeletal abnormalities in Tfr2-knockout mice. We further show that the extracellular domain of Tfr2 binds bone morphogenic proteins (BMPs) and inhibits BMP-2-induced heterotopic ossification by acting as a decoy receptor. These data indicate that Tfr2 limits bone formation by modulating BMP signalling, possibly through direct interaction with BMP either as a receptor or as a co-receptor in complex with other BMP receptors. Finally, the Tfr2 extracellular domain may be effective in the treatment of conditions associated with pathological bone formation.
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All data sets generated during the current study are available from the corresponding author upon reasonable request.
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We would like to thank our technicians for their excellent work. We thank the Core Facility Cellular Imaging of TU Dresden for their support with the confocal microscope and the acquisition of immunofluorescence images and A. Drescher and J. Nickel for critical suggestions regarding SPR analyses. This work was supported by the German Research Foundation (DFG-SFB655 to L.C.H. and U.P.; TRR-67 to V.H. and L.C.H.; µBONE to M.R. and L.C.H.; RA1923/12-1 to M.R.) and MedDrive start-up grants from the Medical Faculty of the Technische Universität Dresden (M.R. and U.B.). M.R. was supported by the Support-the-Best Initiative of the TUD funded through the Excellence initiative of the German Federal and State Governments. J.H.D.B. and G.R.W. received a Wellcome Trust Joint Investigator Award (110141/Z/15/Z and 110140/Z/15/Z). M.U.M. acknowledges support by grants from the Deutsche Forschungsgemeinschaft (SFB1036 and SFB1118).
The Technische Universität Dresden holds a patent for the use of Tfr2-ECD to treat heterotopic ossification and other related bone excess diseases (PCT/EP2018/065846). Moreover, a patent application has been filed at the European Patent Office for the use of Tfr2 blockade for the treatment of bone and haematological diseases (#18 177 441.5, 19.06.2018). M.R., U.B., U.P., and L.C.H. are the inventors of both patents. I.T. is a consultant for Kymab Ltd. The other authors declare no competing interests.
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Rauner, M., Baschant, U., Roetto, A. et al. Transferrin receptor 2 controls bone mass and pathological bone formation via BMP and Wnt signalling. Nat Metab 1, 111–124 (2019). https://doi.org/10.1038/s42255-018-0005-8
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