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Matrix metalloproteinase expression in an experimentally-induced DTH model of multiple sclerosis in the rat CNS
D C Anthony1, K M Miller, S Fearn
1The CNS Inflammation Group, Department of Pharmacology, University of Oxford, UK. daniel.anthony@pharm.ox.ac.uk
Abstract:
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.
Insights
Specific matrix metalloproteinases (MMPs) and TNF-alpha increase in experimental multiple sclerosis lesions. These MMPs contribute to blood-brain barrier breakdown and myelin damage, suggesting therapeutic targets.
Area of Science:
- Neuroimmunology
- Molecular Biology
- Pathogenesis of Multiple Sclerosis
Background:
- Matrix metalloproteinases (MMPs) and TNF-alpha are implicated in central nervous system (CNS) inflammation.
- Their specific roles in the pathogenesis of multiple sclerosis (MS) require further elucidation.
Purpose of the Study:
- To investigate the expression of various MMPs and TNF-alpha in an experimental DTH model of MS.
- To determine the contribution of specific MMPs to CNS damage.
Main Methods:
- Examined mRNA and protein expression of MMPs and TNF-alpha in control and DTH rat brains using RT-PCR and immunohistochemistry.
- Stereotaxically injected purified MMP-7, MMP-8, and MMP-9 into rat brains to assess their effects.
Main Results:
- Significant upregulation of MMP-7, MMP-8, MMP-12, and TNF-alpha mRNA and protein was observed in DTH lesions compared to controls.
- Injected MMP-7, MMP-8, and MMP-9 induced leukocyte recruitment and blood-brain barrier (BBB) breakdown.
- MMP-7 and MMP-9 injections led to myelin loss.
Conclusions:
- Specific MMPs are upregulated in experimental MS lesions and correlate with increased protein levels.
- Upregulated MMPs can directly contribute to BBB disruption, leukocyte infiltration, and myelin damage in the CNS.