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

Martina Rauner, Ulrike Baschant, Antonella Roetto, Rosa Maria Pellegrino, Sandra Rother, Juliane Salbach-Hirsch, Heike Weidner, Vera Hintze, Graeme Campbell, Andreas Petzold, Regis Lemaitre, Ian Henry, Teresita Bellido, Igor Theurl, Sandro Altamura, Silvia Colucci, Martina U. Muckenthaler, Georg Schett, Davide S.K. Komla-Ebri, J. H.Duncan BassettGraham R. Williams, Uwe Platzbecker, Lorenz C. Hofbauer

Research output: Contribution to journalArticle

10 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)111-124
Number of pages14
JournalNature Metabolism
Volume1
Issue number1
DOIs
StatePublished - Jan 1 2019
Externally publishedYes

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology (medical)
  • Internal Medicine
  • Cell Biology

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    Rauner, M., Baschant, U., Roetto, A., Pellegrino, R. M., Rother, S., Salbach-Hirsch, J., Weidner, H., Hintze, V., Campbell, G., Petzold, A., Lemaitre, R., Henry, I., Bellido, T., Theurl, I., Altamura, S., Colucci, S., Muckenthaler, M. U., Schett, G., Komla-Ebri, D. S. K., ... Hofbauer, L. C. (2019). Transferrin receptor 2 controls bone mass and pathological bone formation via BMP and Wnt signalling. Nature Metabolism, 1(1), 111-124. https://doi.org/10.1038/s42255-018-0005-8