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

Rajendran, R.; Böttiger, Gregor; Stadelmann, Christine; Karnati, Srikanth; Berghoff, Martin

doi:10.3390/cells10040884

Cited by 34 publications

(26 citation statements)

References 116 publications

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“…In the cerebellum, these mice showed reduced myelin and axonal degeneration and reduced inflammatory infiltrates compared to controls (Rajendran, Rajendran, et al, 2021). Thus, cell‐specific inactivation of FGFR1 in oligodendrocytes has anti‐inflammatory and neuroprotective effects, and pharmacological inhibition of FGFRs could have therapeutic benefit (Rajendran, Bottiger, et al, 2021).…”

Section: Fgf Signaling In the Brain And Sensory Organsmentioning

confidence: 99%

New developments in the biology of fibroblast growth factors

Ornitz

Itoh

2022

WIREs Mechanisms of Disease

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The fibroblast growth factor (FGF) family is composed of 18 secreted signaling proteins consisting of canonical FGFs and endocrine FGFs that activate four receptor tyrosine kinases (FGFRs 1-4) and four intracellular proteins (intracellular FGFs or iFGFs) that primarily function to regulate the activity of voltagegated sodium channels and other molecules. The canonical FGFs, endocrine FGFs, and iFGFs have been reviewed extensively by us and others. In this review, we briefly summarize past reviews and then focus on new developments in the FGF field since our last review in 2015. Some of the highlights in the past 6 years include the use of optogenetic tools, viral vectors, and inducible transgenes to experimentally modulate FGF signaling, the clinical use of small molecule FGFR inhibitors, an expanded understanding of endocrine FGF signaling, functions for FGF signaling in stem cell pluripotency and differentiation, roles for FGF signaling in tissue homeostasis and regeneration, a continuing elaboration of mechanisms of FGF signaling in development, and an expanding appreciation of roles for FGF signaling in neuropsychiatric diseases.

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Section: Fgf Signaling In the Brain And Sensory Organsmentioning

confidence: 99%

New developments in the biology of fibroblast growth factors

Ornitz

Itoh

2022

WIREs Mechanisms of Disease

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“…In contrast, conditional deletion of either FGF2 or FGFR enhances remyelination in the cuprizone demyelination model at 12 weeks of cuprizone ingestion. Extended and elevated expression of FGF9 causes failure of remyelination [49]. In vitro, inhibition of FGFR in oligodendrocytes enhances myelin protein expression of PLP and CNPase [50].…”

Section: Discussionmentioning

confidence: 99%

Oligodendrocyte-Specific Deletion of FGFR1 Reduces Cerebellar Inflammation and Neurodegeneration in MOG35-55-Induced EAE

Rajendran

Giraldo-Velásquez

et al. 2021

IJMS

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Multiple sclerosis (MS) is a chronic inflammatory and degenerative disease of the central nervous system (CNS). MS commonly affects the cerebellum causing acute and chronic symptoms. Cerebellar signs significantly contribute to clinical disability, and symptoms such as tremor, ataxia, and dysarthria are difficult to treat. Fibroblast growth factors (FGFs) and their receptors (FGFRs) are involved in demyelinating pathologies such as MS. In autopsy tissue from patients with MS, increased expression of FGF1, FGF2, FGF9, and FGFR1 was found in lesion areas. Recent research using mouse models has focused on regions such as the spinal cord, and data on the expression of FGF/FGFR in the cerebellum are not available. In recent EAE studies, we detected that oligodendrocyte-specific deletion of FGFRs results in a milder disease course, less cellular infiltrates, and reduced neurodegeneration in the spinal cord. The objective of this study was to characterize the role of FGFR1 in oligodendrocytes in the cerebellum. Conditional deletion of FGFR1 in oligodendrocytes (Fgfr1ind−/−) was achieved by tamoxifen application, EAE was induced using the MOG35-55 peptide. The cerebellum was analyzed by histology, immunohistochemistry, and western blot. At day 62 p.i., Fgfr1ind−/− mice showed less myelin and axonal degeneration compared to FGFR1-competent mice. Infiltration of CD3(+) T cells, Mac3(+) cells, B220(+) B cells and IgG(+) plasma cells in cerebellar white matter lesions (WML) was less in Fgfr1ind−/−mice. There were no effects on the number of OPC or mature oligodendrocytes in white matter lesion (WML). Expression of FGF2 and FGF9 associated with less myelin and axonal degeneration, and of the pro-inflammatory cytokines IL-1β, IL-6, and CD200 was downregulated in Fgfr1ind−/−mice. The FGF/FGFR signaling protein pAkt, BDNF, and TrkB were increased in Fgfr1ind−/−mice. These data suggest that cell-specific deletion of FGFR1 in oligodendrocytes has anti-inflammatory and neuroprotective effects in the cerebellum in the EAE disease model of MS.

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“…The opposite result is observed when FGFR1 and FGFR2 are knocked out in 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNP)-positive oligodendrocyte lineage cells, which impair remyelination in the same model [ 309 ]. This is likely due to different effects of the cytokine, since bFGF promotes proliferation and migration of OPCs but inhibits oligodendrocyte differentiation [ 310 ]. The restrictive permeability of the BBB being a major limit for administration of large proteins such as growth factors, new approaches to facilitate their crossing, e.g., through the use of nanoparticle transport, have been developed to solve this problem.…”

Section: Neuroprotective Effect Of Drugs Under Developmentmentioning

confidence: 99%

A Narrative Review on Axonal Neuroprotection in Multiple Sclerosis

et al. 2022

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Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) resulting in demyelination and neurodegeneration. The therapeutic strategy is now largely based on reducing inflammation with immunosuppressive drugs. Unfortunately, when disease progression is observed, no drug offers neuroprotection apart from its anti-inflammatory effect. In this review, we explore current knowledge on the assessment of neurodegeneration in MS and look at putative targets that might prove useful in protecting the axon from degeneration. Among them, Bruton’s tyrosine kinase inhibitors, anti-apoptotic and antioxidant agents, sex hormones, statins, channel blockers, growth factors, and molecules preventing glutamate excitotoxicity have already been studied. Some of them have reached phase III clinical trials and carry a great message of hope for our patients with MS.

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

Cited by 34 publications

References 116 publications

New developments in the biology of fibroblast growth factors

New developments in the biology of fibroblast growth factors

Oligodendrocyte-Specific Deletion of FGFR1 Reduces Cerebellar Inflammation and Neurodegeneration in MOG35-55-Induced EAE

A Narrative Review on Axonal Neuroprotection in Multiple Sclerosis

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