Transferrin receptor 2 controls bone mass and pathological bone formation via BMP and Wnt signalling
Open accessAbstract
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.
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TFR2 expression in osteoclasts and osteoblasts places this iron sensor at the crossroads of red cell production, iron homeostasis and bone turnover.
“The recently demonstrated TFR2 expression in osteoclasts and osteoblasts70 places this iron sensor at the crossroads of red cell production, iron homeostasis and bone turnover.”
From Iron metabolism and iron disorders revisited in the hepcidin era (2020) · cites this paper as [70]
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Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625 · see citing works
The Molecular Signatures Database Hallmark Gene Set Collection
Liberzon, A., Birger, C., Thorvaldsdóttir, H., Ghandi, M., Mesirov, J. P., & Tamayo, P. (2015) · Cell Systems · doi:10.1016/j.cels.2015.12.004 · Cited by 13,807 · see citing works
Hepcidin Regulates Cellular Iron Efflux by Binding to Ferroportin and Inducing Its Internalization
Nemeth, E., Tuttle, M. S., Powelson, J., Vaughn, M. B., Donovan, A., Ward, D. M., Ganz, T., & Kaplan, J. (2004) · Science · doi:10.1126/science.1104742 · Cited by 4,803 · see citing works
A Red carpet for iron metabolism
Muckenthaler, M. U., Rivella, S., Hentze, M. W., & Galy, B. (2017) · Cell · doi:10.1016/j.cell.2016.12.034 · Cited by 1,319 · see citing works
Self-citationBone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression
Babitt, J. L., Huang, F. W., Wrighting, D. M., Xia, Y., Sidis, Y., Samad, T. A., Campagna, J. A., Chung, R. T., Schneyer, A. L., Woolf, C. J., et al. (2006) · Nature Genetics · doi:10.1038/ng1777 · Cited by 1,026 · see citing works
D’Alessio, F., Hentze, M. W., & Muckenthaler, M. U. (2012) · Journal of Hepatology · doi:10.1016/j.jhep.2012.06.015 · Cited by 200 · see citing works
Cortical-Bone Fragility — Insights from sFRP4 Deficiency in Pyle’s Disease
Simsek Kiper, P. O., Saito, H., Gori, F., Unger, S., Hesse, E., Yamana, K., Kiviranta, R., Solban, N., Liu, J., Brommage, R., et al. (2016) · New England Journal of Medicine · doi:10.1056/nejmoa1509342 · Cited by 151 · see citing works
Altamura, S., Kessler, R., Gröne, H.-J., Gretz, N., Hentze, M. W., Galy, B., & Muckenthaler, M. U. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.07.007 · Cited by 119 · see citing works
Mayeur, C., Leyton, P. A., Kolodziej, S. A., Yu, B., & Bloch, K. D. (2014) · Blood · doi:10.1182/blood-2014-04-572644 · Cited by 74 · see citing works
Shen, G. S., Yang, Q., Jian, J. L., Zhao, G. Y., Liu, L. L., Wang, X., Zhang, W., Huang, X., & Xu, Y. J. (2014) · Calcified Tissue International · doi:10.1007/s00223-014-9845-8 · Cited by 51 · see citing works
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Iron metabolism and iron disorders revisited in the hepcidin era
Camaschella, C., Nai, A., & Silvestri, L. (2020) · Haematologica · doi:10.3324/haematol.2019.232124 · Cited by 734 · see citing works
“The recently demonstrated TFR2 expression in osteoclasts and osteoblasts 70 places this iron sensor at the crossroads of red cell production, iron homeostasis and bone turnover.”
Hyperthyroidism-driven bone loss depends on BMP receptor Bmpr1a expression in osteoblasts
Lademann, F., Rijntjes, E., Köhrle, J., Tsourdi, E., Hofbauer, L. C., & Rauner, M. (2024) · Communications Biology · doi:10.1038/s42003-024-06227-0 · Cited by 8 · see citing works
- Authors
- 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., Bassett, J. H. D., Williams, G. R., Platzbecker, U., & Hofbauer, L. C.
- Affiliations
- Technische Universität Dresden (DE)
- University of Turin (IT)
- Max Bergmann Center of Biomaterials (DE)
- Hamburg University of Technology (DE)
- Biotechnologisches Zentrum (DE)
- Max Planck Institute of Molecular Cell Biology and Genetics (DE)
- Indiana University Indianapolis (US)
- Innsbruck Medical University (AT)
- Heidelberg University (DE)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Imperial College London (GB)
- University Hospital Leipzig (DE)
- Center for Regenerative Therapies Dresden (DE)
- Corresponding author
- Rauner, Martina
- ORCID
- Rauner, Martina
- Baschant, Ulrike
- Roetto, Antonella
- Rother, Sandra
- Salbach-Hirsch, Juliane
- Weidner, Heike
- Hintze, Vera
- Campbell, Graeme
- Henry, Ian
- Bellido, Teresita
- Theurl, Igor
- Altamura, Sandro
- Colucci, Silvia
- Muckenthaler, Martina U.
- Schett, Georg
- Komla-Ebri, Davide S. K.
- Bassett, J. H. Duncan
- Williams, Graham R.
- Platzbecker, Uwe
- Hofbauer, Lorenz C.
- Venue
- Nature Metabolism
- Published
- 2019-01-07
- Volume
- 1
- Issue
- 1
- Pages
- 111-124
- ISSN
- 2522-5812 (ISSN-L)
- PMC
- PMC6420074
- OpenAlex
- W2901508573
- Cited by
- 87
- References
- 10
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 13 · 2023: 6 · 2022: 16 · 2021: 14 · 2020: 14 · 2019: 8
- FWCI
- 3.20
- Type
- journal article
- Language
- en
- Update notices
- correction (2019-04-12)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
- Spiral (Imperial College London) (submittedVersion)
- tub.dok (Hamburg University of Technology) (submittedVersion)
- Funders
- U.S. Department of Veterans Affairs (IK6 BX004596, I01 BX002104)
- Wellcome Trust (101123WILLIAMS, 101123, 110141/Z/15/Z, 110140, 110140/Z/15/Z, 110141)
- Deutsche Forschungsgemeinschaft (SFB 655)
- Technische Universität Dresden
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR059357)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Health Sciences › Medicine › Rheumatology › Heterotopic Ossification and Related Conditions
- Keywords
- transferrin receptor 2, bone homeostasis, bone formation, bone mass, BMP signaling, Wnt signaling, sclerostin, p38 MAPK, osteoblasts, heterotopic ossification, decoy receptor, BMP-2, iron homeostasis, bone mineralization
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