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FGF/FGFR Pathways in Multiple Sclerosis and in Its Disease Models
Ranjithkumar Rajendran1, Gregor Böttiger1, Christine Stadelmann2
1Experimental Neurology, Department of Neurology, University of Giessen, Klinikstrasse 33, 35385 Giessen, Germany.
Abstract:
Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the central nervous system (CNS) affecting more than two million people worldwide. In MS, oligodendrocytes and myelin sheaths are destroyed by autoimmune-mediated inflammation, while remyelination is impaired. Recent investigations of post-mortem tissue suggest that Fibroblast growth factor (FGF) signaling may regulate inflammation and myelination in MS. FGF2 expression seems to correlate positively with macrophages/microglia and negatively with myelination; FGF1 was suggested to promote remyelination. In myelin oligodendrocyte glycoprotein (MOG)35-55-induced experimental autoimmune encephalomyelitis (EAE), systemic deletion of FGF2 suggested that FGF2 may promote remyelination. Specific deletion of FGF receptors (FGFRs) in oligodendrocytes in this EAE model resulted in a decrease of lymphocyte and macrophage/microglia infiltration as well as myelin and axon degeneration. These effects were mediated by ERK/Akt phosphorylation, a brain-derived neurotrophic factor, and downregulation of inhibitors of remyelination. In the first part of this review, the most important pharmacotherapeutic principles for MS will be illustrated, and then we will review recent advances made on FGF signaling in MS. Thus, we will suggest application of FGFR inhibitors, which are currently used in Phase II and III cancer trials, as a therapeutic option to reduce inflammation and induce remyelination in EAE and eventually MS.
Insights
Fibroblast growth factor (FGF) signaling influences inflammation and remyelination in multiple sclerosis (MS). Inhibiting FGF receptors (FGFRs) may reduce inflammation and promote myelin repair in MS.
Area of Science:
- Neuroimmunology
- Neurodegenerative diseases
- Cell signaling
Background:
- Multiple sclerosis (MS) is a chronic CNS disease characterized by inflammation, demyelination, and neurodegeneration.
- Oligodendrocyte and myelin damage is central to MS pathology, with impaired remyelination.
- Fibroblast growth factor (FGF) signaling is implicated in MS, with FGF2 potentially promoting inflammation and FGF1 aiding remyelination.
Purpose of the Study:
- To review the role of FGF signaling in MS.
- To explore the therapeutic potential of targeting FGF signaling pathways for MS treatment.
Main Methods:
- Analysis of post-mortem MS tissue.
- Investigation of FGF2 and FGF1 roles in MOG35-55-induced experimental autoimmune encephalomyelitis (EAE) in mice.
- Specific deletion of FGF receptors (FGFRs) in oligodendrocytes in the EAE model.
- Assessment of inflammatory cell infiltration, myelin and axon integrity, and molecular signaling pathways (ERK/Akt, BDNF).
Main Results:
- FGF2 expression correlated with inflammation and inversely with myelination in MS.
- Targeting FGFRs in oligodendrocytes in EAE reduced inflammation and demyelination.
- FGFR inhibition modulated ERK/Akt phosphorylation, brain-derived neurotrophic factor levels, and remyelination inhibitor expression.
Conclusions:
- FGF signaling plays a complex role in MS pathogenesis, influencing both inflammation and remyelination.
- Inhibitors of FGF receptors (FGFRs), currently in cancer trials, represent a potential therapeutic strategy for MS.
- Targeting FGFRs may reduce CNS inflammation and promote remyelination in MS and EAE models.
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