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Nat Metab. 2019 Jan;1(1):111-124. doi: 10.1038/s42255-018-0005-8. Epub 2019 Jan 7.

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

Author information

1
Department of Medicine III, Technische Universität Dresden, Dresden, Germany.
2
Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany.
3
Department of Clinical and Biological Science, University of Torino, Torino, Italy.
4
Institute of Materials Science, Max Bergmann Center of Biomaterials, Technische Universität Dresden, Dresden, Germany.
5
Institute of Biomechanics, Hamburg University of Technology, Hamburg, Germany.
6
Deep Sequencing, Biotechnology Center, Technische Universität Dresden, Dresden, Germany.
7
Max Planck Institute for Cell Biology and Genetics, Protein Unit, Dresden, Germany.
8
Max Planck Institute for Cell Biology and Genetics, Scientific Computing Facility, Dresden, Germany.
9
Department of Anatomy and Cell Biology and Department of Medicine, Division of Endocrinology, School of Medicine, Indiana University, Indianapolis, IN, USA.
10
Department of Internal Medicine VI, Medical University of Innsbruck, Innsbruck, Austria.
11
Department of Pediatric Hematology, Oncology and Immunology, University of Heidelberg, Heidelberg, Germany.
12
Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nuremberg (FAU) and University Hospital Erlangen, Erlangen, Germany.
13
Molecular Endocrinology Laboratory, Department of Medicine, Imperial College London, London W12 0NN, United Kingdom.
14
Department of Medicine II, University Clinic Leipzig, Germany.
15
German Cancer Consortium (DKTK) Partner Site Dresden, Dresden, Germany.
16
Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany.
#
Contributed equally

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 signaling 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 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 signaling, possibly through direct interaction with BMP either as a receptor or as a co-receptor in a complex with other BMP receptors. Finally, the Tfr2 extracellular domain may be effective in the treatment of conditions associated with pathological bone formation.

Conflict of interest statement

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 hematological diseases (#18 177 441.5, 19.06.2018). MR, UB, UP, and LCH are the inventors of both patents. IT is a consultant for Kymab Ltd. The other authors declare no competing interests.

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