title: Matrix metalloproteinases and their tissue inhibitors in cuprizone-induced demyelination and remyelination of brain white and gray matter.
abstract: Apart from their involvement in the pathogenesis of demyelinating diseases such as multiple sclerosis, there is emerging evidence that matrix metalloproteinases (MMPs) also promote remyelination. We investigated region-specific expression patterns of 11 MMPs and 4 tissueinhibitors of metalloproteinases (TIMPs) in the cuprizone murine demyelination model. Messenger RNA (mRNA) was extracted at different time points of exposure to cuprizone from microdissected samples of corpus callosum, cortex, and ex vivo isolated microglia and analyzedusing quantitative reverse transcription-polymerase chain reaction.Matrix metalloproteinase 12 and TIMP-1 mRNA were significantly upregulated versus age-matched controls in both areas during demyelination and remyelination. Matrix metalloproteinases 3, 11, and 14 mRNA were upregulated only in white matter during remyelination. Matrix metalloproteinase 24 mRNA was downregulated during both demyelination and remyelination. To identify potential cellular sources of the MMPs and TIMPs, we isolated microglia and detected high MMP-12and TIMP-2 mRNA upregulation at the peak of demyelination.By immunohistochemistry, MMP-3 protein was localized in astrocytes and MMP-12 was identified in microglia, astrocytes, and cells of oligodendrocyte lineage. These findings suggest that MMPs and TIMPs have roles in the regulation of demyelination and remyelination in thismodel. Moreover, differences in the expression levels of these genesbetween white and gray matter reveal region-specific molecularmechanisms.
authors.affiliation: Department of Neurology, Hannover Medical School, Hannover, Germany.
authors.forename: Jelena
authors.initials: J
authors.lastname: Skuljec
authors.forename: Viktoria
authors.initials: V
authors.lastname: Gudi
authors.forename: Reiner
authors.initials: R
authors.lastname: Ulrich
authors.forename: Konstantin
authors.initials: K
authors.lastname: Frichert
authors.forename: Ozlem
authors.initials: O
authors.lastname: Yildiz
authors.forename: Refik
authors.initials: R
authors.lastname: Pul
authors.forename: Elke V
authors.initials: EV
authors.lastname: Voss
authors.forename: Kirsten
authors.initials: K
authors.lastname: Wissel
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Baumgärtner
authors.forename: Martin
authors.initials: M
authors.lastname: Stangel
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D003337:Corpus Callosum / Q000187:drug effects / Q000473:pathology; D003471:Cuprizone / Q000633:toxicity; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000473:pathology*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008297:Male; D020782:Matrix Metalloproteinases / Q000145:classification / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D042282:Microdissection / Q000379:methods; D017628:Microglia / Q000187:drug effects / Q000473:pathology; D008996:Monoamine Oxidase Inhibitors / Q000633:toxicity; D012333:RNA, Messenger / Q000378:metabolism; D018709:Statistics, Nonparametric; D019714:Tissue Inhibitor of Metalloproteinases / Q000145:classification / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; D005904:Glial Fibrillary Acidic Protein; D008996:Monoamine Oxidase Inhibitors; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; D003471:Cuprizone; D020782:Matrix Metalloproteinases