Publication
Title
Conditional mouse models support the role of SLC39A14 (ZIP14) in Hyperostosis Cranialis Interna and in bone homeostasis
Author
Abstract
Hyperostosis Cranialis Interna (HCI) is a rare bone disorder characterized by progressive intracranial bone overgrowth at the skull. Here we identified by whole-exome sequencing a dominant mutation (L441R) in SLC39A14 (ZIP14). We show that L441R ZIP14 is no longer trafficked towards the plasma membrane and excessively accumulates intracellular zinc, resulting in hyper-activation of cAMP-CREB and NFAT signaling. Conditional knock-in mice overexpressing L438R Zip14 in osteoblasts have a severe skeletal phenotype marked by a drastic increase in cortical thickness due to an enhanced endosteal bone formation, resembling the underlying pathology in HCI patients. Remarkably, L438R Zip14 also generates an osteoporotic trabecular bone phenotype. The effects of osteoblastic overexpression of L438R Zip14 therefore mimic the disparate actions of estrogen on cortical and trabecular bone through osteoblasts. Collectively, we reveal ZIP14 as a novel regulator of bone homeostasis, and that manipulating ZIP14 might be a therapeutic strategy for bone diseases.
Language
English
Source (journal)
PLoS genetics. - San Francisco, Calif.
Publication
San Francisco, Calif. : 2018
ISSN
1553-7390
1553-7404
Volume/pages
14 :4 (2018) , 29 p.
Article Reference
e1007321
ISI
000431115700029
Pubmed ID
29621230
Medium
E-only publicatie
Full text (Publisher's DOI)
Full text (open access)
UAntwerpen
Faculty/Department
Research group
Project info
Gα subunits as intracellular partners of WNT16 in osteoblasts – a functional analysis.
Systems biology for the functional validation of genetic determinants of skeletal diseases (SYBIL).
Identification and characterization of the gene underlying hyperostosis cranialis interna.
Evaluation of the role of LRP4 in the regulation of Wnt/Bcatenin dependent Wnt signalling and bone formation.
Publication type
Subject
Affiliation
Publications with a UAntwerp address
External links
Web of Science
Record
Identification
Creation 26.04.2018
Last edited 17.09.2021
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