Effects of FGFR Tyrosine Kinase Inhibition in OLN-93 Oligodendrocytes.

Ranjithkumar Rajendran,Christine Stadelmann,Niklas Dentzien,Gregor Böttiger,Srikanth Karnati,Bischand Sharifi,Vinothkumar Rajendran,Süleyman Ergün,Martin Berghoff

doi:10.3390/cells10061318

Ranjithkumar Rajendran, Christine Stadelmann + Show 7 more

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https://doi.org/10.3390/cells10061318

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Journal: Cells	Publication Date: May 25, 2021
Citations: 8	License type: CC BY 4.0

Affiliation: University of Giessen, University of Würzburg

Abstract

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 MOG35–55-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.

Highlights

Demyelination of the central nervous system (CNS) causes degeneration of axons [1]associated with permanent disability [2,3,4]
We recently showed that OL-specific deletion of either FGFR1 or FGFR2 resulted in a less severe disease course in MOG35–55-induced EAE [16,17]
Detrimental effects of FGF receptor (FGFR) signaling in OLs on inflammation, myelin and axons were found in this disease model, highlighting the importance for the investigation of FGFR signaling in these myelin-producing cells

Summary

Introduction

Demyelination of the central nervous system (CNS) causes degeneration of axons [1]associated with permanent disability [2,3,4]. The pivotal impediment for remyelination in MS is most likely not the recruitment of oligodendrocyte progenitor cells (OPCs) to lesions, but OPCs‘ inability to differentiate into mature myelin-producing oligodendrocytes (OLs) [8,9]. Growth factors have been associated with the differentiation of oligodendrocytes in demyelinating pathologies. These include brain derived neurotrophic factor (BDNF), nerve growth factor (NGF), insulin-like growth factor (IGF), platelet derived growth factor (PDGF), ciliary neurotrophic factor (CNTF) and FGF [10,11]. FGF1 is expressed in oligodendrocytes, astrocytes, microglia/macrophages and infiltrating lymphocytes [12]. FGF2 is mainly found in microglia/macrophages [13], whereas FGF9 is expressed in oligodendrocytes and astrocytes [14]. In the cerebrospinal fluid (CSF), FGF2 levels were increased in patients with MS, and their highest expression was found in relapse [15]

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