Conditional mouse models support the role of SLC39A14 (ZIP14) in Hyperostosis Cranialis Interna and in bone homeostasis.

• Main Authors: Gretl Hendrickx, Vere M Borra, Ellen Steenackers, Timur A Yorgan, Christophe Hermans, Eveline Boudin, Jérôme J Waterval, Ineke D C Jansen, Tolunay Beker Aydemir, Niels Kamerling, Geert J Behets, Christine Plumeyer, Patrick C D'Haese, Björn Busse, Vincent Everts, Martin Lammens, Geert Mortier, Robert J Cousins, Thorsten Schinke, Robert J Stokroos, Johannes J Manni, Wim Van Hul
• Format: Article
• Language: English
• Published: Public Library of Science (PLoS) 2018-04-01
• Series: PLoS Genetics
• Online Access: http://europepmc.org/articles/PMC5903675?pdf=render
• ISSN: 1553-7390; 1553-7404

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.