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

Research output: Contribution to journalResearch articleContributedpeer-review



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.


Original languageEnglish
Pages (from-to)111-124
Number of pages14
JournalNature metabolism
Issue number1
Publication statusPublished - Jan 2019

External IDs

PubMed 30886999
PubMedCentral PMC6420074
Scopus 85073645062
ORCID /0000-0002-8691-8423/work/142235989
ORCID /0000-0001-9599-8632/work/142241736
ORCID /0000-0002-5611-9903/work/142244030
ORCID /0009-0001-6045-3349/work/150330109
ORCID /0000-0001-7097-9953/work/142255928