Transferrin receptor 2 controls bone mass and pathological bone formation via BMP and Wnt signaling
Author(s)
Type
Journal Article
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.
Date Issued
2019-01
Date Acceptance
2018-10-19
Citation
Nature Metabolism, 2019, 1 (1), pp.111-124
ISSN
2522-5812
Publisher
Nature Research
Start Page
111
End Page
124
Journal / Book Title
Nature Metabolism
Volume
1
Issue
1
Copyright Statement
© The Author(s), under exclusive licence to Springer Nature Limited 2019. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
Sponsor
Wellcome Trust
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/30886999
Grant Number
110141/Z/15/Z
Publication Status
Published
Coverage Spatial
England
Date Publish Online
2019-01-07