FGF/FGFR Pathways in Multiple Sclerosis and in Its Disease Models.

Ranjithkumar Rajendran,Martin Berghoff,Gregor Böttiger,Srikanth Karnati,Christine Stadelmann

doi:10.3390/cells10040884

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.

Highlights

An increase of ERK/Akt phosphorylation and increased expression of the brain derived neurotrophic factor (BDNF) and its receptor TrkB were observed, further LINGO1, an inhibitor of remyelination, was downregulated [108]. These findings suggest that oligodendrocytes can elicit an intrinsic regulatory response upregulating the BDNF/TrkB
Since only Akt was raised in the chronic phase of EAE, other pro-myelinating mediators than ERK or BDNF/TrkB may account for decreased myelin degeneration
In the EAE disease model, intrathecal gene therapy with FGF2 and systemic deletion of FGF2 indicated a beneficial role of FGF2 in the chronic phase of EAE, though inconsistent findings depending on the exposure to FGF2, and a strong dependence on the microenvironment suggests functional diversity of this signaling cascade in the adult

Summary

Multiple Sclerosis Is a Chronic Disease of the Central Nervous System

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Multiple sclerosis is a chronic inflammatory and neurodegenerative disease of the CNS. The most common condition is called relapsing remitting multiple sclerosis (RRMS), which affects individuals mostly early in their adult life (mean age at onset of approximately 30 years), around 20% of patients have late-onset RRMS with an onset of more than 40 years [5]. Polypharmacy, the condition of using multiple medications, was more common in older RRMS patients with high BMI [6]. Primary progressive MS is a rare disease type affecting 10–15% of patients. In Germany, the disease causes significant disability, and dependent direct (healthcare) and indirect costs (absence from work, early retirement) of up to 60,000 EUR per patient in a year [13]

Inflammatory Destruction of Oligodendrocytes and Myelin Sheaths

Current Disease Modifying Treatment and Symptomatic Therapy for MS

FGF2 May Be Neuroprotective in EAE

Findings

Summary