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Impaired proteoglycan glycosylation, elevated TGF-β signaling, and abnormal osteoblast differentiation as the basis for bone fragility in a mouse model for gerodermia osteodysplastica

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Mundlos,  Stefan
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;
Institut für Medizinische Genetik und Humangenetik, Charité -Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany;
Berlin-Brandenburg Center for Regenerative Therapies, Charité -Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany;

/persons/resource/persons50391

Kornak,  Uwe
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;
Institut für Medizinische Genetik und Humangenetik, Charité -Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany;
Berlin-Brandenburg Center for Regenerative Therapies, Charité -Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany;

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Citation

Chan, W. L., Steiner, M., Witkos, T., Egerer, J., Busse, B., Mizumoto, S., et al. (2018). Impaired proteoglycan glycosylation, elevated TGF-β signaling, and abnormal osteoblast differentiation as the basis for bone fragility in a mouse model for gerodermia osteodysplastica. PLoS Genetics, 14(3): e1007242. doi:10.1371/journal.pgen.1007242.


Cite as: http://hdl.handle.net/21.11116/0000-0003-5CA5-C
Abstract
Author summary Gerodermia osteodysplastica (GO) is segmental progeroid disorder affecting connective tissues and bone, leading to extreme bone fragility. The cause are loss-of-function mutations in the Golgi protein GORAB, whose function has been only partially unravelled. Using several mouse models and patient-derived primary cells we elucidate that loss of Gorab elicits a defect in proteoglycan glycanation, which is associated with collagen disorganization in dermis and bone. We also found evidence for TGF-β upregulation and enhanced downstream signalling. If these changes occur in mesenchymal stem cells or early osteoblasts they impair osteoblast differentiation resulting in cortical thinning and spontaneous fractures. We thus match GO mechanistically with also phenotypically overlapping progeroid connective tissue disorders with glycanation defects.