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Fibroblast growth factor signalling in multiple sclerosis: inhibition of myelination and induction of pro-inflammatory environment by FGF9

Lindner, Maren and Thümmler, Katja and Arthur, Ariel and Brunner, Sarah and Elliott, Christina and McElroy, Daniel and Mohan, Hema and Williams, Anna and Edgar, Julia M. and Schuh, Cornelia and Stadelmann, Christine and Barnett, Susan C. and Lassmann, Hans and Mücklisch, Steve and Mudaliar, Manikhandan and Schaeren-Wiemers, Nicole and Meinl, Edgar and Linington, Christopher. (2015) Fibroblast growth factor signalling in multiple sclerosis: inhibition of myelination and induction of pro-inflammatory environment by FGF9. Brain, 138 (7). pp. 1875-1893.

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Official URL: http://edoc.unibas.ch/56511/

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Abstract

Remyelination failure plays an important role in the pathophysiology of multiple sclerosis, but the underlying cellular and molecular mechanisms remain poorly understood. We now report actively demyelinating lesions in patients with multiple sclerosis are associated with increased glial expression of fibroblast growth factor 9 (FGF9), which we demonstrate inhibits myelination and remyelination in vitro. This inhibitory activity is associated with the appearance of multi-branched 'pre-myelinating' MBP+ / PLP+ oligodendrocytes that interact with axons but fail to assemble myelin sheaths; an oligodendrocyte phenotype described previously in chronically demyelinated multiple sclerosis lesions. This inhibitory activity is not due to a direct effect of FGF9 on cells of the oligodendrocyte lineage but is mediated by factors secreted by astrocytes. Transcriptional profiling and functional validation studies demonstrate that these include effects dependent on increased expression of tissue inhibitor of metalloproteinase-sensitive proteases, enzymes more commonly associated with extracellular matrix remodelling. Further, we found that FGF9 induces expression of Ccl2 and Ccl7, two pro-inflammatory chemokines that contribute to recruitment of microglia and macrophages into multiple sclerosis lesions. These data indicate glial expression of FGF9 can initiate a complex astrocyte-dependent response that contributes to two distinct pathogenic pathways involved in the development of multiple sclerosis lesions. Namely, induction of a pro-inflammatory environment and failure of remyelination; a combination of effects predicted to exacerbate axonal injury and loss in patients.
Faculties and Departments:03 Faculty of Medicine
03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Neurobiology (Schaeren-Wiemers)
UniBasel Contributors:Schaeren-Wiemers, Nicole
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Oxford University Press
ISSN:0006-8950
e-ISSN:1460-2156
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
Identification Number:
Last Modified:04 Dec 2017 11:09
Deposited On:04 Dec 2017 11:09

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