title: Matrix metalloproteinase-12 deficiency ameliorates the clinical course and demyelination in Theiler's murine encephalomyelitis.
abstract: 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.
authors.affiliation: Department of Pathology, University of Veterinary Medicine Hannover, Bünteweg 17, 30559, Hannover, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Hansmann
authors.forename: Vanessa
authors.initials: V
authors.lastname: Herder
authors.forename: Arno
authors.initials: A
authors.lastname: Kalkuhl
authors.forename: Verena
authors.initials: V
authors.lastname: Haist
authors.forename: Ning
authors.initials: N
authors.lastname: Zhang
authors.forename: Dirk
authors.initials: D
authors.lastname: Schaudien
authors.forename: Ulrich
authors.initials: U
authors.lastname: Deschl
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Baumgärtner
authors.forename: Reiner
authors.initials: R
authors.lastname: Ulrich
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000503:physiopathology; D001933:Brain Stem / Q000473:pathology / Q000648:ultrastructure; D003711:Demyelinating Diseases / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism*; D004195:Disease Models, Animal; D055032:Electron Microscope Tomography; D004679:Encephalomyelitis / Q000150:complications* / Q000821:virology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D052119:Lysosomal-Associated Membrane Protein 2 / Q000378:metabolism; D053508:Matrix Metalloproteinase 12 / Q000172:deficiency* / Q000235:genetics; D019278:Matrix Metalloproteinase 3 / Q000172:deficiency / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000008:administration & dosage / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D046228:Microarray Analysis; D009185:Myelin Proteins / Q000378:metabolism; D000070798:Nogo Proteins; D013681:Tegmentum Mesencephali / Q000473:pathology / Q000648:ultrastructure; D017945:Theilovirus / Q000472:pathogenicity*; D013997:Time Factors
chemical_list: D005904:Glial Fibrillary Acidic Protein; D052119:Lysosomal-Associated Membrane Protein 2; D009185:Myelin Proteins; D000070798:Nogo Proteins; C000603201:Rtn4 protein, mouse; D019278:Matrix Metalloproteinase 3; C511769:Mmp3 protein, mouse; D020780:Matrix Metalloproteinase 9; D053508:Matrix Metalloproteinase 12