Expression of ADAMTS-1, -4, -5 and TIMP-3 in normal and multiple sclerosis CNS white matter.
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.
Haddock
G
G
Biomedical Research Centre, Sheffield Hallam University, Howard Street, Sheffield S1 1WB, UK. g.haddock@shu.ac.uk
Cross
A K
AK
Plumb
J
J
Surr
J
J
Buttle
D J
DJ
Bunning
R A D
RA
Woodroofe
M N
MN
D051722:ADAM Proteins / Q000235:genetics* / Q000378:metabolism; D000071097:ADAMTS1 Protein; D000071121:ADAMTS4 Protein; D000071116:ADAMTS5 Protein; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D001921:Brain / Q000201:enzymology / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020528:Multiple Sclerosis, Chronic Progressive / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D009413:Nerve Fibers, Myelinated / Q000201:enzymology* / Q000473:pathology; D011348:Procollagen N-Endopeptidase / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
D012333:RNA, Messenger; C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3; D051722:ADAM Proteins; D000071097:ADAMTS1 Protein; C103859:ADAMTS1 protein, human; D000071116:ADAMTS5 Protein; C121532:ADAMTS5 protein, human; D011348:Procollagen N-Endopeptidase; D000071121:ADAMTS4 Protein; C000603918:ADAMTS4 protein, human