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Expression of ADAMTS-1, -4, -5 and TIMP-3 in normal and multiple sclerosis CNS white matter

Biomedical Research Centre, Sheffield Hallam University, Howard Street, Sheffield S1 1WB, UK, Division of Genomic Medicine, School of Medicine & Biomedical Sciences, E-Floor, The Medical School, Beech Hill Road, Sheffield S10 2RX, UK, g.haddock{at}shu.ac.uk

A K Cross

Biomedical Research Centre, Sheffield Hallam University, Howard Street, Sheffield S1 1WB, UK, Division of Genomic Medicine, School of Medicine & Biomedical Sciences, E-Floor, The Medical School, Beech Hill Road, Sheffield S10 2RX, UK

J Plumb

Biomedical Research Centre, Sheffield Hallam University, Howard Street, Sheffield S1 1WB, UK

J Surr

Biomedical Research Centre, Sheffield Hallam University, Howard Street, Sheffield S1 1WB, UK, Division of Genomic Medicine, School of Medicine & Biomedical Sciences, E-Floor, The Medical School, Beech Hill Road, Sheffield S10 2RX, UK

D J Buttle

Division of Genomic Medicine, School of Medicine & Biomedical Sciences, E-Floor, The Medical School, Beech Hill Road, Sheffield S10 2RX, UK

R AD Bunning

Biomedical Research Centre, Sheffield Hallam University, Howard Street, Sheffield S1 1WB, UK

M N Woodroofe

Biomedical Research Centre, Sheffield Hallam University, Howard Street, Sheffield S1 1WB, UK

ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) -1, -4 and -5 proteases have been identified in the CNS at the mRNA level. These glutamyl endopeptidases, inhibited by tissue inhibitor of metalloproteinases (TIMP)-3, are key enzymes in the degradation of the aggregating chondroitin sulphate proteoglycans (CSPGs), and may therefore play a role in CNS extracellular matrix (ECM) changes in multiple sclerosis (MS). We have investigated ADAMTS and TIMP-3 expression in normal and MS CNS white matter by real-time RT-PCR, western blotting and immunohistochemistry. We report for the first time the presence of ADAMTS-1, -4 and -5 in normal and MS white matter. Levels of ADAMTS-1 and -5 mRNA were decreased in MS compared to normal tissue, with no significant change in ADAMTS-4 mRNA levels. Protein levels of ADAMTS-4 were significantly higher in MS tissue compared to normal tissue. Immunohistochemical studies demonstrated that ADAMTS-4 was associated predominantly with astrocytes with increased expression within MS lesions. TIMP-3 mRNA was significantly decreased in MS compared to controls. These studies suggest a role for ADAMTS-4 in the pathogenesis of MS. Further studies on the activity of ADAMTS-4 will enable a better understanding of its role in the turnover of the ECM of white matter in MS.

Key Words: ADAMTS • extracellular matrix • multiple sclerosis • TIMP-3

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