The extracellular matrix in multiple sclerosis pathology

Horssen, Jack van; Dijkstra, Christine D.; Vries, Helga E. de

doi:10.1111/j.1471-4159.2007.04897.x

Cited by 97 publications

(101 citation statements)

References 90 publications

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“…We observed a progressive disaggregation of the ECM with the formation of vacuoles as well as vanishing of brain parenchyma on one hand, and a patchy accumulation of fibronectin, glycosaminoglycans, and mucopolysaccharides on the other hand, the later assumably caused by local inflammatory processes. A similar up-regulation of ECM molecules has been reported in MS and other inflammatory CNS diseases (12,(23)(24)(25). However, we were not able to identify a single and unique ECM component causing the cuprizone effect on viscoelastic properties alone.…”

Section: Discussionmentioning

confidence: 50%

“…However, we were not able to identify a single and unique ECM component causing the cuprizone effect on viscoelastic properties alone. This is not surprising: The current state of knowledge assigns a functional role to ECM molecules in the CNS (directing maturation, degeneration, and repair processes) more than keeping a simple structural/mechanical role (23,26). The local up-regulation of several ECM proteins during cuprizone feeding, as we show, might contribute to the degree of structural dysintegrity within the corpus callosum, additionally to the vacuolization and loss of parenchyma.…”

Section: Discussionmentioning

confidence: 83%

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Demyelination reduces brain parenchymal stiffness quantified in vivo by magnetic resonance elastography

Schregel

Tysiak

Garteiser

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

204

186

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The detection of pathological tissue alterations by manual palpation is a simple but essential diagnostic tool, which has been applied by physicians since the beginnings of medicine. Recently, the virtual "palpation" of the brain has become feasible using magnetic resonance elastography, which quantifies biomechanical properties of the brain parenchyma by analyzing the propagation of externally elicited shear waves. However, the precise molecular and cellular patterns underlying changes of viscoelasticity measured by magnetic resonance elastography have not been investigated up to date. We assessed changes of viscoelasticity in a murine model of multiple sclerosis, inducing reversible demyelination by feeding the copper chelator cuprizone, and correlated our results with detailed histological analyses, comprising myelination, extracellular matrix alterations, immune cell infiltration and axonal damage. We show firstly that the magnitude of the complex shear modulus decreases with progressive demyelination and global extracellular matrix degradation, secondly that the loss modulus decreases faster than the dynamic modulus during the destruction of the corpus callosum, and finally that those processes are reversible after remyelination. magnetic resonance imaging | elasticity imaging | tissue integrity P alpation of the brain, a hands-on experience long exclusive to neurosurgeons and pathologists detecting brain pathology, has recently become a domain for physicists and radiologists: Using magnetic resonance elastography (MRE), it is possible today to noninvasively assess the biomechanical properties of brain parenchyma in vivo. In MRE, viscoelasticity describes the tendency of tissue to resist deformation, thus translating the subjective tactile information gained from palpation into a quantifiable objective measure. These properties can be acquired by analyzing the propagation of low-frequency shear waves, which are mechanically elicited in an organ of interest (1, 2).Recent preliminary studies described distinct viscoelastic characteristics of the brain parenchyma in healthy subjects as well as changes by aging and brain pathology, underlining the applicability and relevance of cerebral MRE (3, 4). During physiological aging, there was evidence for a brain parenchymal "liquification" reflected in the decrease of solid-fluid behavior of the tissue (5). In patients suffering from multiple sclerosis (MS), a significant decrease of cerebral viscoelasticity was noted already in early disease stages compared with healthy controls (6).However, despite a rising collection of in vivo viscoelasticity data, no study has yet directly correlated viscoelastic parameters assessed via MRE with histopathological analyses. Thus, the question on how in vivo mechanical properties translate into cellular and molecular conditions has remained open.Magnetic resonance imaging (MRI) has emerged as most important paraclinical tool for the diagnosis and monitoring of neuroinflammatory diseases like MS, as reflected by current diagnostic ...

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Section: Discussionmentioning

confidence: 50%

Section: Discussionmentioning

confidence: 83%

Demyelination reduces brain parenchymal stiffness quantified in vivo by magnetic resonance elastography

Schregel

Tysiak

Garteiser

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

204

186

View full text Add to dashboard Cite

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“…a-f Significant differences between the groups as detected by Mann-Whitney U tests are marked by bars and asterisks (p B 0.05) changes of ECM molecules revealed an upregulation of fibronectin at all time points of the observation period, while laminin-1, laminin alpha-4, laminin-5, and collagen I, III, and IV were transiently upregulated. ECM molecules produced by endothelial cells and perivascular astrocytes like fibronectin [68], laminins [35], or collagen IV [68] belong to the group of basement membrane (BM) components, which are involved in glial scar formation [27]. BM molecules play an important role in the regulation of BBB/BSCB permeability, so that alterations in their composition will effect infiltration of inflammatory cells [57,67].…”

Section: Mmp-3 In Demyelination and Inflammationmentioning

confidence: 99%

Matrix metalloproteinase-12 deficiency ameliorates the clinical course and demyelination in Theiler’s murine encephalomyelitis

Hansmann¹,

Herder²,

Kalkuhl

et al. 2012

Acta Neuropathol

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Matrix metalloproteinases (MMPs) are a family of extracellular proteases involved in the pathogenesis of demyelinating diseases like multiple sclerosis (MS). The aim of the present study was to investigate whether MMPs induce direct myelin degradation, leukocyte infiltration, disruption of the blood-brain barrier (BBB), and/or extracellular matrix remodeling in the pathogenesis of Theiler's murine encephalomyelitis (TME), a virus-induced model of MS. During the demyelinating phase of TME, the highest transcriptional upregulation was detected for Mmp12, followed by Mmp3. Mmp12 (-/-) mice showed reduced demyelination, macrophage infiltration, and motor deficits compared with wild-type- and Mmp3 knock-out mice. However, BBB remained unaltered, and the amount of extracellular matrix deposition was similar in knock-out mice and wild-type mice. Furthermore, stereotaxic injection of activated MMP-3, -9, and -12 into the caudal cerebellar peduncle of adult mice induced a focally extensive primary demyelination prior to infiltration of inflammatory cells, as well as a reduction in the number of oligodendrocytes and a leakage of BBB. All these results demonstrate that MMP-12 plays an essential role in the pathogenesis of TME, most likely due to its primary myelin- or oligodendrocyte-toxic potential and its role in macrophage extravasation, whereas there was no sign of BBB damage or alterations to extracellular matrix remodeling/deposition. Thus, interrupting the MMP-12 cascade may be a relevant therapeutic approach for preventing chronic progressive demyelination.

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“…Astrocyte end feet have close contact with parenchymal basement membrane around vessels, contributing to maintenance of the BBB through induction of tight junctions between endothelial cells [140]. Astroglia also produce components of the extracellular matrix, such as collagens, laminins, fibronectins, hyaluronan, chondroitin sulfate, and heparin sulfate [141][142][143], which constitute the basal lamina around vessels. Astroglia constitutively express the membranebound death ligand, CD95L, and can induce CD95L-mediated apoptosis of infiltrating T cells [144,145].…”

Section: Neuroprotective Aspectsmentioning

confidence: 99%

Multiple Sclerosis: Etiology and Mechanism, with Special Reference to Asians

Kira

2016

Neuroimmunological Diseases

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Multiple sclerosis (MS) is a disease that targets myelin in the central nervous system (CNS). It is thought to be an autoimmune disease but this is not yet proven. Genome-wide association studies have revealed many susceptibility genes for MS, and the functions of these genes are mostly immune-related, supporting the autoimmune hypothesis. Increased numbers of T cells showing inter-and intramolecular epitope spreading against myelin proteins; increased cerebrospinal fluid (CSF) levels of interferon (IFN)-γ, interleukin (IL)-17, and downstream pro-inflammatory cytokines; exacerbation of disease following IFN-γ administration; and increased percentages of T helper (Th)1 cells secreting IFN-γ and of Th17 cells secreting IL-17 at relapse all support T-cell involvement in MS lesion formation. B-cell infiltration in the CNS parenchyma is not prominent, while B-cell follicles in the meninges appear to have a close correlation with subpial demyelination, suggesting an involvement of autoantibodies. However, no specific autoantibodies for MS have been detected, although anti-aquaporin-4 antibodies are a specific biomarker for neuromyelitis optica (NMO). We reported the extensive loss of connexins (Cxs) 43, 32, and 47 in acute lesions in patients with Baló's concentric sclerosis, MS, and NMO. Such loss of astroglial and oligodendroglial Cxs could induce widespread disruption of the glial syncytium, leading to failure of energy source transfer. Thus, loss of Cxs in acute MS lesions may contribute to extensive lesion formation. In the Japanese population, HLA-DRB1*0405 is the most common susceptibility allele for non-NMO MS. DRB1*0405 carriers comprise >40 % of all Japanese MS patients, and this proportion is higher in younger generations. HLA-DRB1*0405-positive MS patients show characteristic features, such as younger age at onset, fewer brain lesions, fewer CSF IgG abnormalities, and a slower progression. The recent increase in the number of MS patients in this subgroup may explain the overall decrease in onset age, as shown by the fourth nationwide survey of Japanese MS patients. Therefore, changes in environmental factors may have increased susceptibility to MS in Japanese populations with certain genetic backgrounds.

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The extracellular matrix in multiple sclerosis pathology

Cited by 97 publications

References 90 publications

Demyelination reduces brain parenchymal stiffness quantified in vivo by magnetic resonance elastography

Demyelination reduces brain parenchymal stiffness quantified in vivo by magnetic resonance elastography

Matrix metalloproteinase-12 deficiency ameliorates the clinical course and demyelination in Theiler’s murine encephalomyelitis

Multiple Sclerosis: Etiology and Mechanism, with Special Reference to Asians

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