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Transferrin receptor 2 controls bone mass and pathological bone formation via BMP and Wnt signalling

Nature Metabolism volume 1, pages 111–124 (2019)Cite this article

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An Author Correction to this article was published on 12 April 2019

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Abstract

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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Fig. 1: Tfr2 deficiency results in high bone mass.
Fig. 2: High bone mass in Tfr2–/– mice is independent of iron overload and the hepatic function of Tfr2.
Fig. 3: Deficiency of Tfr2 in osteogenic cells increases bone mass.
Fig. 4: Downregulation of BMP signalling and Wnt inhibitors in Tfr2 deficiency.
Fig. 5: High bone mass in Tfr2 deficiency is rescued by overexpressing SOST or reactivating MAPK signalling.
Fig. 6: Tfr2 binds BMP ligands and blocks heterotopic ossification.

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Data availability

All data sets generated during the current study are available from the corresponding author upon reasonable request.

Change history

  • 12 April 2019

    In the version of this article initially published, affiliation 14 was incorrect, and Deutsche Forschungsgemeinschaft grants SFB1036 and SFB1118 were missing from the Acknowledgements. The errors have been corrected in the HTML and PDF versions of the article.

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Acknowledgements

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).

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Author notes

  1. These authors contributed equally: M. Rauner, U. Baschant.

Authors and Affiliations

  1. Department of Medicine III, Technische Universität Dresden, Dresden, Germany

    Martina Rauner, Ulrike Baschant, Juliane Salbach-Hirsch, Heike Weidner & Lorenz C. Hofbauer

  2. Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany

    Martina Rauner, Ulrike Baschant, Juliane Salbach-Hirsch, Heike Weidner, Uwe Platzbecker & Lorenz C. Hofbauer

  3. Department of Clinical and Biological Science, University of Torino, Torino, Italy

    Antonella Roetto & Rosa Maria Pellegrino

  4. Institute of Materials Science, Max Bergmann Center of Biomaterials, Technische Universität Dresden, Dresden, Germany

    Sandra Rother & Vera Hintze

  5. Institute of Biomechanics, Hamburg University of Technology, Hamburg, Germany

    Graeme Campbell

  6. Deep Sequencing, Biotechnology Center, Technische Universität Dresden, Dresden, Germany

    Andreas Petzold

  7. Max Planck Institute for Cell Biology and Genetics, Protein Unit, Dresden, Germany

    Regis Lemaitre

  8. Max Planck Institute for Cell Biology and Genetics, Scientific Computing Facility, Dresden, Germany

    Ian Henry

  9. Department of Anatomy and Cell Biology and Department of Medicine, Division of Endocrinology, School of Medicine, Indiana University, Indianapolis, IN, USA

    Teresita Bellido

  10. Department of Internal Medicine VI, Medical, University of Innsbruck, Innsbruck, Austria

    Igor Theurl

  11. Department of Pediatric Hematology, Oncology and Immunology, University of Heidelberg, Heidelberg, Germany

    Sandro Altamura, Silvia Colucci & Martina U. Muckenthaler

  12. Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nuremberg (FAU) and University Hospital Erlangen, Erlangen, Germany

    Georg Schett

  13. Molecular Endocrinology Laboratory, Department of Medicine, Imperial College London, London, United Kingdom

    Davide S. K. Komla-Ebri, J. H. Duncan Bassett & Graham R. Williams

  14. Department of Medicine I, Technische Universität Dresden, Dresden, Germany

    Uwe Platzbecker

  15. German Cancer Consortium (DKTK) Partner Site Dresden, Dresden, Germany

    Uwe Platzbecker & Lorenz C. Hofbauer

  16. Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany

    Lorenz C. Hofbauer

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Contributions

M.R., U.B., A.R., J.S-H., S.R., U.P., and L.C.H. designed experiments. M.R., U.B., A.R., R.M.P., J.S.-H., H.W., S.R., G.C., A.P., R.L., I.H., S.C., and D.K.E. performed experiments and analysed data. T.B., S.A., S.C., M.U.M., and I.T. provided mouse bone samples. M.R., U.B., A.R., J.S.-H., H.W., S.R., V.H., I.H., T.B., M.U.M., J.H.D.B., G.R.W., G.S., I.T., U.P., and L.C.H. interpreted the data and provided critical comments on the manuscript. M.R., U.B., and L.C.H. wrote the manuscript. All authors provided critical review of the manuscript.

Corresponding author

Correspondence to Martina Rauner.

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Competing interests

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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Supplementary Table 1

Summary of the results obtained from gene ontology analysis

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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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