Fibroblast growth factor signalling in multiple sclerosis: inhibition of myelination and induction of pro-inflammatory environment by FGF9

Lindner, Maren; Thümmler, Katja; Arthur, Ariel; Brunner, Sarah; Elliott, Carl; McElroy, Daniel; Mohan, Hema; Williams, Anna; Edgar, Julia M.; Schuh, Cornelia; Stadelmann, Christine; Barnett, Susan C.; Lassmann, H.; Mücklisch, Steve; Mudaliar, Manikhandan; Schaeren‐Wiemers, Nicole; Meinl, Edgar; Linington, Christopher

doi:10.1093/brain/awv102

Cited by 54 publications

(83 citation statements)

References 85 publications

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“…FGF9 was found in active demyelinating lesions in patients with MS, and was made responsible for tissue damage, lesion formation through activating proinflammatory cytokine and chemokine production in the CNS. In vitro FGF9 inhibited myelination and remyelination .…”

Section: Discussionmentioning

confidence: 99%

Oligodendroglial fibroblast growth factor receptor 1 gene targeting protects mice from experimental autoimmune encephalomyelitis through ERK/AKT phosphorylation

et al. 2017

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Fibroblast growth factors (FGFs) exert diverse biological effects by binding and activation of specific fibroblast growth factor receptors (FGFRs). FGFs and FGFRs have been implicated in demyelinating pathologies including multiple sclerosis. In vitro activation of the FGF2/FGFR1 pathway results in downregulation of myelin proteins. FGF1, 2 and 9 have been shown to be involved in the pathology of multiple sclerosis. Recent studies on the function of oligodendroglial FGFR1 in a model of toxic demyelination showed that deletion of FGFR1 led to increased remyelination and preservation of axonal density and an increased number of mature oligodendrocytes. In the present study the in vivo function of oligodendroglial FGFR1 was characterized using an oligodendrocyte-specific genetic approach in the most frequently used model of multiple sclerosis the MOG -induced EAE. Oligodendroglial FGFR1 deficient mice (referred to as Fgfr1 ) showed a significantly ameliorated disease course in MOG -induced EAE. Less myelin and axonal loss, and reduced lymphocyte and macrophage/microglia infiltration were found in Fgfr1 mice. The reduction in disease severity in Fgfr1 mice was accompanied by ERK/AKT phosphorylation, and increased expression of BDNF and TrkB. Reduced proinflammatory cytokine and chemokine expression was seen in Fgfr1 mice compared with control mice. Considering that FGFR inhibitors are used in cancer trials, the oligodendroglial FGFR1 pathway may provide a new target for therapy in multiple sclerosis.

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Section: Discussionmentioning

confidence: 99%

Oligodendroglial fibroblast growth factor receptor 1 gene targeting protects mice from experimental autoimmune encephalomyelitis through ERK/AKT phosphorylation

et al. 2017

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“…Quantification was carried out using CellProfiler Image Analysis software (Broad Institute) (Carpenter et al, 2006;Lindner et al, 2015).…”

Section: Myelination and Opc/oligodendrocyte (Ol) Quantificationmentioning

confidence: 99%

Low sulfated heparins target multiple proteins for central nervous system repair

McCanney

McGrath

Otto

et al. 2018

Glia

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The lack of endogenous repair following spinal cord injury (SCI) accounts for the frequent permanent deficits for which effective treatments are absent. Previously, we demonstrated that low sulfated modified heparin mimetics (LS‐mHeps) attenuate astrocytosis, suggesting they may represent a novel therapeutic approach. mHeps are glycomolecules with structural similarities to resident heparan sulfates (HS), which modulate cell signaling by both sequestering ligands, and acting as cofactors in the formation of ligand–receptor complexes. To explore whether mHeps can affect the myelination and neurite outgrowth necessary for repair after SCI, we created lesioned or demyelinated neural cell co‐cultures and exposed them with a panel of mHeps with varying degrees and positions of their sulfate moieties. LS‐mHep7 enhanced neurite outgrowth and myelination, whereas highly sulfated mHeps (HS‐mHeps) had attenuating effects. LS‐mHeps had no effects on myelination or neurite extension in developing, uninjured myelinating cultures, suggesting they might exert their proregenerating effects by modulating or sequestering inhibitory factors secreted after injury. To investigate this, we examined conditioned media from cultures using chemokine arrays and conducted an unbiased proteomics approach by applying TMT‐LC/MS to mHep7 affinity purified conditioned media from these cultures. Multiple protein factors reported to play a role in damage or repair mechanisms were identified, including amyloid betaA4. Amyloid beta peptide (1–42) was validated as an important candidate by treating myelination cultures and shown to inhibit myelination. Thus, we propose that LS‐mHeps exert multiple beneficial effects on mechanisms supporting enhanced repair, and represent novel candidates as therapeutics for CNS damage.

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“…Fibroblast growth factor 9 (FGF9) is a 26 kDa secreted protein in the fibroblast growth factor family that is essential and sufficient for development. Mutations in Fgf9 have been reported to be associated with several human diseases, such as prostate cancer, endometriosis, and multiple sclerosis . In addition, studies have confirmed that Fgf9 is a crucial regulatory gene of the lung mesenchyme .…”

Section: Introductionmentioning

confidence: 94%

FGF9 modulates Schwann cell myelination in developing nerves and induces a pro‐inflammatory environment during injury

Deng

Duan

et al. 2018

J of Cellular Biochemistry

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Myelin sheath is critical for the proper functioning of the peripheral nervous system (PNS), which allows the effective conduction of nerve impulses. Fibroblast growth factor 9 (FGF9) is an autocrine and paracrine protein in the fibroblast growth factor family that regulates cell differentiation and proliferation. Fgf9 Schwann cell (SC) conditional knockout mice were developed to detect the role of FGF9 in the PNS. In our study, the absence of Fgf9 led to delayed myelination in early development. The expression of mature SC-related genes decreased, and the expression of genes associated with immature SCs increased in the Fgf9 knockout mice. These data were consistent with the morphology and praxeology we observed during the development of the peripheral nerves. Extracellular-regulated kinases 1/2 (ERK1/2) are key signals for myelination, and our results showed that Fgf9 ablation led to the inactivation of ERK1/2. Further research was performed to detect the role of FGF9 in peripheral nerve injury. In superoxide dismutase 1-G93A mice with Fgf9 SC knockout, we found that Fgf9 ablation inhibited the expressions of Cd68, Il-1β, and Cd86, which contributed to the degeneration of the axon and myelin sheath.

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Fibroblast growth factor signalling in multiple sclerosis: inhibition of myelination and induction of pro-inflammatory environment by FGF9

Cited by 54 publications

References 85 publications

Oligodendroglial fibroblast growth factor receptor 1 gene targeting protects mice from experimental autoimmune encephalomyelitis through ERK/AKT phosphorylation

Oligodendroglial fibroblast growth factor receptor 1 gene targeting protects mice from experimental autoimmune encephalomyelitis through ERK/AKT phosphorylation

Low sulfated heparins target multiple proteins for central nervous system repair

FGF9 modulates Schwann cell myelination in developing nerves and induces a pro‐inflammatory environment during injury

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