Conditional mouse models support the role of SLC39A14 (ZIP14) in Hyperostosis Cranialis Interna and in bone homeostasis
Standard
Conditional mouse models support the role of SLC39A14 (ZIP14) in Hyperostosis Cranialis Interna and in bone homeostasis. / Hendrickx, Gretl; Borra, Vere M; Steenackers, Ellen; Yorgan, Timur A; Hermans, Christophe; Boudin, Eveline; Waterval, Jérôme J; Jansen, Ineke D C; Aydemir, Tolunay Beker; Kamerling, Niels; Behets, Geert J; Plumeyer, Christine; D'Haese, Patrick C; Busse, Björn; Everts, Vincent; Lammens, Martin; Mortier, Geert; Cousins, Robert J; Schinke, Thorsten; Stokroos, Robert J; Manni, Johannes J; Van Hul, Wim.
in: PLOS GENET, Jahrgang 14, Nr. 4, 04.2018, S. e1007321.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Conditional mouse models support the role of SLC39A14 (ZIP14) in Hyperostosis Cranialis Interna and in bone homeostasis
AU - Hendrickx, Gretl
AU - Borra, Vere M
AU - Steenackers, Ellen
AU - Yorgan, Timur A
AU - Hermans, Christophe
AU - Boudin, Eveline
AU - Waterval, Jérôme J
AU - Jansen, Ineke D C
AU - Aydemir, Tolunay Beker
AU - Kamerling, Niels
AU - Behets, Geert J
AU - Plumeyer, Christine
AU - D'Haese, Patrick C
AU - Busse, Björn
AU - Everts, Vincent
AU - Lammens, Martin
AU - Mortier, Geert
AU - Cousins, Robert J
AU - Schinke, Thorsten
AU - Stokroos, Robert J
AU - Manni, Johannes J
AU - Van Hul, Wim
PY - 2018/4
Y1 - 2018/4
N2 - 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.
AB - 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.
KW - Journal Article
U2 - 10.1371/journal.pgen.1007321
DO - 10.1371/journal.pgen.1007321
M3 - SCORING: Journal article
C2 - 29621230
VL - 14
SP - e1007321
JO - PLOS GENET
JF - PLOS GENET
SN - 1553-7404
IS - 4
ER -