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

Autor:	Christine Plumeyer, Jérôme Waterval, Ellen Steenackers, Tolunay Beker Aydemir, Robert Cousins, Wim Van Hul, Geert Mortier, Vincent Everts, Timur A. Yorgan, Bjoern Busse, Thorsten Schinke, Vere Borra, Martin Lammens, Gretl Hendrickx, Christophe Hermans, Patrick C. D'Haese, Niels Kamerling, Ineke D. C. Jansen, Johannes J. Manni, Eveline Boudin, Robert J. Stokroos, Geert J. Behets
Přispěvatelé:	Periodontology, Oral Cell Biology, Parodontologie (OII, ACTA), Orale Celbiologie (ORM, ACTA)
Jazyk:	angličtina
Rok vydání:	2018
Předmět:	0301 basic medicine Cancer Research Physiology Organogenesis Osteoclasts Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12] DISEASE ZINC TRANSPORTER ZIP14 Animal Cells Medicine and Health Sciences Homeostasis Femur Musculoskeletal System Cation Transport Proteins Cells Cultured Genetics (clinical) Connective Tissue Cells Mice Knockout Skull Base Genetics & Heredity DENSITY DISTRIBUTION TRANSGENIC MICE NFAT Animal Models Hyperostosis Phenotype Cell biology Zinc medicine.anatomical_structure Experimental Organism Systems Connective Tissue HEALTH Cellular Types Anatomy Hyperostosis cranialis interna Life Sciences & Biomedicine Osteosclerosis Research Article Signal Transduction lcsh:QH426-470 medicine.drug_class Mouse Models Biology Research and Analysis Methods Osteocytes Cell Line 03 medical and health sciences All institutes and research themes of the Radboud University Medical Center Model Organisms SDG 3 - Good Health and Well-being Genetics medicine Animals Humans Bone Molecular Biology Skeleton Ecology Evolution Behavior and Systematics Osteoblasts Bone Development Science & Technology RECEPTOR Skull HEK 293 cells Biology and Life Sciences Cell Biology GENE Mice Inbred C57BL Disease Models Animal lcsh:Genetics Biological Tissue HEK293 Cells BOUND IRON 030104 developmental biology ACRODERMATITIS-ENTEROPATHICA Estrogen Mutation Human medicine Physiological Processes Organism Development EHLERS-DANLOS-SYNDROME Developmental Biology
Zdroj:	PLoS Genetics, Vol 14, Iss 4, p e1007321 (2018) Plos Genetics, 14, PLoS genetics Hendrickx, G, Borra, V M, Steenackers, E, Yorgan, T A, Hermans, C, Boudin, E, Waterval, J J, Jansen, I D C, Aydemir, T B, Kamerling, N, Behets, G J, Plumeyer, C, D'Haese, P C, Busse, B, Everts, V, Lammens, M, Mortier, G, Cousins, R J, Schinke, T, Stokroos, R J, Manni, J J & van Hul, W 2018, ' Conditional mouse models support the role of SLC39A14 (ZIP14) in Hyperostosis Cranialis Interna and in bone homeostasis ', PLoS Genetics, vol. 14, no. 4, e1007321, pp. e1007321 . https://doi.org/10.1371/journal.pgen.1007321 PLoS Genetics, 14(4):e1007321. Public Library of Science PLOS Genetics, 14(4):e1007321. Public Library of Science PLoS Genetics Plos Genetics, 14, 4, pp.
ISSN:	1553-7404 1553-7390
DOI:	10.1371/journal.pgen.1007321
Popis:	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. Author summary Osteoporosis is a skeletal disorder affecting hundreds of millions of people, and is characterized by a low bone mineral density (BMD) and increased susceptibility to fracture. Genetic factors are the greatest determinants of BMD, but only a small fraction of these have been identified through genome-wide association studies. Studying rare, monogenic skeletal disorders is therefore an interesting strategy to identify genes with a putative large effect on BMD. Hyperostosis Cranialis Interna (HCI) is a rare monogenic disorder resulting in bone overgrowth exclusively at the skull, for which the underlying genetic cause was previously mapped to a region on chromosome 8. Our study demonstrates that HCI results from a mutation in SLC39A14 (ZIP14), resulting in trafficking defects of ZIP14 and an aberrant cellular zinc homeostasis. Conditional mouse models demonstrate primary actions of Zip14 through osteoblasts, resulting in a HCI-like phenotype in the long bones and reveal estrogen-mimicking and PTH-opposing effects of Zip14 on bone homeostasis. This study designates ZIP14 as a novel regulator of BMD, and that manipulating ZIP14 might be a therapeutic strategy for complex bone diseases, like osteoporosis.
Databáze:	OpenAIRE
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