MMP-2 null mice exhibit an early onset and severe experimental autoimmune encephalomyelitis due to an increase in MMP-9 expression and activity.
Matrix metalloproteinase-2 (MMP-2; gelatinase A) is known to degrade a broad range of extracellular matrix components and chemokines, and has important roles in the processes of cell migration, invasion, and involution during development, as well as during tumor growth and metastasis and in inflammation and repair. To better elucidate the roles of this matrix metalloproteinase in the development and progression of experimental autoimmune encephalomyelitis, we used MMP-2-deficient (KO) mice. Surprisingly, we found that MMP-2 KO mice exhibited an earlier onset and more severe disease than did their wild-type (WT) counterparts. WT mice engrafted with MMP-2 KO bone marrow exhibited a similar earlier onset and more severe clinical disease score than WT mice engrafted with WT bone marrow. Lymphocytes derived from MMP-2 KO mice exhibited increased transmigration through endothelial cell monolayers as well as through collagen type IV and laminin-coated BD BIOCOAT inserts, which correlated with a 3-fold increase in expression of MMP-9 and was abrogated by inhibition of MMP activity. We demonstrated a correlation between expression levels of MMP-9 and MT1-MMP expression and suggest a signaling pathway involving tethering of MMP-2 to MT1-MMP as a modulator of MMP-9 expression. Last, we discuss other possible MMP-2-mediated mechanisms which may contribute to the observed phenotype.
Esparza
Jordi
J
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Kruse
Meghan
M
Lee
Janet
J
Michaud
Michael
M
Madri
Joseph A
JA
D017668:Age of Onset; D000818:Animals; D001485:Basement Membrane / Q000378:metabolism; D001812:Blood-Brain Barrier; D001921:Brain / Q000276:immunology; D017252:CD3 Complex / Q000032:analysis; D002465:Cell Movement; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000201:enzymology* / Q000209:etiology* / Q000473:pathology; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D053511:Matrix Metalloproteinase 14; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000502:physiology*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016176:T-Lymphocyte Subsets / Q000737:chemistry; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology
D017252:CD3 Complex; C507096:Mmp14 protein, mouse; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D053511:Matrix Metalloproteinase 14