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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

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.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0003-5CA5-C Version Permalink: http://hdl.handle.net/21.11116/0000-0003-5CA6-B
Genre: Journal Article

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 Creators:
Chan, Wing Lee, Author
Steiner, Magdalena, Author
Witkos, Tomasz, Author
Egerer, Johannes, Author
Busse, Björn, Author
Mizumoto, Shuji, Author
Pestka, Jan M., Author
Zhang, Haikuo, Author
Hausser, Ingrid, Author
Khayal, Layal Abo, Author
Ott, Claus-Eric, Author
Kolanczyk, Mateusz, Author
Willie, Bettina, Author
Schinke, Thorsten, Author
Paganini, Chiara, Author
Rossi, Antonio, Author
Sugahara, Kazuyuki, Author
Amling, Michael, Author
Knaus, Petra, Author
Chan, Danny, Author
Lowe, Martin, AuthorMundlos, Stefan1, 2, 3, Author              Kornak, Uwe1, 2, 3, Author               more..
Affiliations:
1Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              
2Institut 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, ou_persistent22              
3Berlin-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, ou_persistent22              

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 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.

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Language(s): eng - English
 Dates: 2018-02-052018-03-212018
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1371/journal.pgen.1007242
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Title: PLoS Genetics
  Other : PLoS Genet.
Source Genre: Journal
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Publ. Info: San Francisco, CA : Public Library of Science
Pages: - Volume / Issue: 14 (3) Sequence Number: e1007242 Start / End Page: - Identifier: ISSN: 1553-7390
CoNE: https://pure.mpg.de/cone/journals/resource/1000000000017180