MATRIX METALLOPROTEINASE EXPRESSION IN AN EXPERIMENTALLY-INDUCED DTH MODEL OF MULTIPLE-SCLEROSIS IN THE RAT CNS

In an experimentally-induced DTH model of MS, we examined mRNA and pro tein expression of a range of MMPs and of TNF alpha to establish the c ontribution that individual MMPs might make to the pathogenesis. In co ntrol rat brain, mRNA for all of the MMPs examined was detectable. How ever, by immunohistochemistry, only MMP-2 could be detected. In the DT H lesions, significant increases in the level of mRNA expression were observed for MMP-7, MMP-8, MMP-12, and TNF alpha. Where expression of MMP mRNA was increased, there was a corresponding increase in protein expression detected by immunohistochemistry. To determine whether the upregulated MMPs could invoke destructive events in the CNS, highly pu rified activated MMP-7, MMP-8, and MMP-9 were stereotaxically injected into the brain parenchyma. All provoked recruitment of leukocytes and BBB breakdown. In addition, MMPs 7 and 9 induced loss of myelin stain ing. In conclusion, specific MMPs are upregulated in DTH lesions; for the most part, measurement of mRNA was a predictor of increased protei n expression. From our injections of MMPs, it is clear that the upregu lated MMPs in the DTH lesions could participate in the disruption of t he BBB, leukocyte recruitment, and tissue damage. (C) 1998 Elsevier Sc ience B.V. All rights reserved.