J Biol Chem 2002 Feb 5;
D'Souza CA, Mak B, Moscarello MA.
Department of Structural Biology and Biochemistry, Hospital for Sick Children, Toronto, Ontario M5G 1X8.
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 (MS).
To determine if up-regulation of MMP-3 (stromelysin-1) was a causative factor during development of demyelination, we have examined the expression of MMP-3 mRNA and protein in brain tissue of a spontaneously demyelinating mouse model over-expressing DM20 (ND4 line) prior to and during 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 disease onset and was co-ordinately expressed with the DM20 transgene.
Stromelysin-1 protein levels were also up-regulated, as was TIMP-1 (tissue inhibitor of metalloproteinase-1, an in vivo regulator of stromelysin-1) mRNA.
When we crossed our ND4 mice with a line of transgenic mice which over-expressed 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 disease onset.