The up-regulation of stromelysin-1 (MMP-3) in a spontaneously demyelinating transgenic mouse precedes onset of disease.
The matrix metalloproteinases (MMPs) are a family of endoproteinases that degrade various components of the extracellular matrix and have been implicated in the pathogenesis of multiple sclerosis. To determine whether up-regulation of MMP-3, or stromelysin-1, was a causative factor during the development of demyelination, we have examined the expression of MMP-3 mRNA and protein in brain tissue of a spontaneously demyelinating mouse model overexpressing DM20 (ND4 line) prior to and during the progression of disease. Stromelysin-1, but not other MMP mRNA was elevated approximately 10-fold in transgenic mice between 5 days and 1 month of age, more than 2 months before the onset of disease, and was coordinately expressed with the DM20 transgene. Stromelysin-1 protein levels were also up-regulated as was tissue inhibitor of metalloproteinase-1 (TIMP-1), an in vivo regulator of stromelysin-1 mRNA. When we crossed our ND4 mice with a line of transgenic mice overexpressing TIMP-1 in brain, clinical signs in these mice were attenuated, and the level of stromelysin-1 protein was reduced. Thus, in this transgenic model of demyelinating disease up-regulation of DM20, MMP-3, and TIMP-1 represent important changes in the chemical pathogenesis in brain, which precede the onset of disease.
D'Souza
Cheryl A
CA
Department of Structural Biology, The Hospital for Sick Children, Toronto, Canada.
Mak
Baldwin
B
Moscarello
Mario A
MA
D000367:Age Factors; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004195:Disease Models, Animal; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D006863:Hydrogen-Ion Concentration; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis*; D051379:Mice; D008822:Mice, Transgenic; D018991:Myelin Proteolipid Protein / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism* / Q000502:physiology; D009419:Nerve Tissue Proteins; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014018:Tissue Distribution; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*; D019076:Transgenes; D015854:Up-Regulation
D018076:DNA, Complementary; D018991:Myelin Proteolipid Protein; D009419:Nerve Tissue Proteins; C047516:Plp1 protein, mouse; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D012313:RNA; D019278:Matrix Metalloproteinase 3