Effects of FGFR tyrosine kinase inhibition in OLN-93 oligodendrocytes

Please always quote using this URN: urn:nbn:de:bvb:20-opus-239600
  • Fibroblast growth factor (FGF) signaling is involved in the pathogenesis of multiple sclerosis (MS). Data from neuropathology studies suggest that FGF signaling contributes to the failure of remyelination in MS. In MOG\(_{35–55}\)-induced EAE, oligodendrocyte-specific deletion of FGFR1 and FGFR2 resulted in a less severe disease course, reduced inflammation, myelin and axon degeneration and changed FGF/FGFR and BDNF/TrkB signaling. Since signaling cascades in oligodendrocytes could not be investigated in the EAE studies, we here aimed toFibroblast growth factor (FGF) signaling is involved in the pathogenesis of multiple sclerosis (MS). Data from neuropathology studies suggest that FGF signaling contributes to the failure of remyelination in MS. In MOG\(_{35–55}\)-induced EAE, oligodendrocyte-specific deletion of FGFR1 and FGFR2 resulted in a less severe disease course, reduced inflammation, myelin and axon degeneration and changed FGF/FGFR and BDNF/TrkB signaling. Since signaling cascades in oligodendrocytes could not be investigated in the EAE studies, we here aimed to characterize FGFR-dependent oligodendrocyte-specific signaling in vitro. FGFR inhibition was achieved by application of the multi-kinase-inhibitor dovitinib and the FGFR1/2/3-inhibitor AZD4547. Both substances are potent inhibitors of FGF signaling; they are effective in experimental tumor models and patients with malignancies. Effects of FGFR inhibition in oligodendrocytes were studied by immunofluorescence microscopy, protein and gene analyses. Application of the tyrosine kinase inhibitors reduced FGFR1, phosphorylated ERK and Akt expression, and it enhanced BDNF and TrkB expression. Furthermore, the myelin proteins CNPase and PLP were upregulated by FGFR inhibition. In summary, inhibition of FGFR signaling in oligodendrocytes can be achieved by application of tyrosine kinase inhibitors. Decreased phosphorylation of ERK and Akt is associated with an upregulation of BDNF/TrkB signaling, which may be responsible for the increased production of myelin proteins. Furthermore, these data suggest that application of FGFR inhibitors may have the potential to promote remyelination in the CNS.show moreshow less

Download full text files

Export metadata

Additional Services

Share in Twitter Search Google Scholar Statistics
Metadaten
Author: Ranjithkumar Rajendran, Gregor Böttiger, Niklas Dentzien, Vinothkumar Rajendran, Bischand Sharifi, Süleyman Ergün, Christine Stadelmann, Srikanth Karnati, Martin Berghoff
URN:urn:nbn:de:bvb:20-opus-239600
Document Type:Journal article
Faculties:Medizinische Fakultät / Institut für Anatomie und Zellbiologie
Language:English
Parent Title (English):Cells
ISSN:2073-4409
Year of Completion:2021
Volume:10
Issue:6
Article Number:1318
Source:Cells (2021) 10:6, 1318. https://doi.org/10.3390/cells10061318
DOI:https://doi.org/10.3390/cells10061318
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Tag:AZD4547; FGFR signaling; dovitinib; multiple sclerosis; myelin; oligodendrocytes
Release Date:2022/08/11
Date of first Publication:2021/05/25
Licence (German):License LogoCC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International