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Brain. 2015 Jul;138(Pt 7):1875-93. doi: 10.1093/brain/awv102. Epub 2015 Apr 22.

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

Author information

1 Institute of Infection, Immunity and Inflammation, University of Glasgow, UK
1 Institute of Infection, Immunity and Inflammation, University of Glasgow, UK.
2 Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland.
3 Institute of Clinical Neuroimmunology, Ludwig-Maximilians-Universität, Munich, Germany.
4 MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK.
5 Centre for Brain Research, Medical University of Vienna, Vienna, Austria.
6 Department of Neuropathology, Georg August University, Göttingen, Germany.
7 Department of Computer Science, Chemnitz University of Technology, Chemnitz, Germany.
8 Glasgow Polyomics, College of Medical, Veterinary and Life Science, University of Glasgow, UK.


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.


FGF; chemokines; inflammation; multiple sclerosis (MS); remyelination

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