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 protein expression of a range of MMPs and of TNFalpha to establish the contribution that individual MMPs might make to the pathogenesis. In control rat brain, mRNA for all of the MMPs examined was detectable. However, by immunohistochemistry, only MMP-2 could be detected. In the DTH lesions, significant increases in the level of mRNA expression were observed for MMP-7, MMP-8, MMP-12, and TNFalpha. 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 purified 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 staining. In conclusion, specific MMPs are upregulated in DTH lesions; for the most part, measurement of mRNA was a predictor of increased protein expression. From our injections of MMPs, it is clear that the upregulated MMPs in the DTH lesions could participate in the disruption of the BBB, leukocyte recruitment, and tissue damage.
The CNS Inflammation Group, Department of Pharmacology, University of Oxford, UK. daniel.anthony@pharm.ox.ac.uk
D C
DC
Anthony
K M
KM
Miller
S
S
Fearn
M J
MJ
Townsend
G
G
Opdenakker
G M
GM
Wells
J M
JM
Clements
S
S
Chandler
A J
AJ
Gearing
V H
VH
Perry
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000502:physiology; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism*; D006968:Hypersensitivity, Delayed / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D007267:Injections; D007962:Leukocytes / Q000502:physiology; D008297:Male; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D009103:Multiple Sclerosis / Q000378:metabolism / Q000473:pathology; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew
D012333:RNA, Messenger; D008666:Metalloendopeptidases