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

• Published in: Multiple sclerosis 2006-08, Vol.12 (4), p.386-396
• Main Authors: Haddock, G, Cross, A K, Plumb, J, Surr, J, Buttle, D J, Bunning, R AD, Woodroofe, M N
• Format: Article
• Language: English
• Subjects: ADAM Proteins - genetics; ADAM Proteins - metabolism; ADAMTS1 Protein; ADAMTS4 Protein; ADAMTS5 Protein; Adult; Aged; Aged, 80 and over; Biological and medical sciences; Blotting, Western; Brain - enzymology; Brain - pathology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Female; Humans; Immunomodulators; Male; Medical sciences; Middle Aged; Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis; Multiple Sclerosis, Chronic Progressive - metabolism; Multiple Sclerosis, Chronic Progressive - pathology; Multiple Sclerosis, Chronic Progressive - physiopathology; Nerve Fibers, Myelinated - enzymology; Nerve Fibers, Myelinated - pathology; Neurology; Pharmacology. Drug treatments; Procollagen N-Endopeptidase - genetics; Procollagen N-Endopeptidase - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - analysis; Tissue Inhibitor of Metalloproteinase-3 - genetics; Tissue Inhibitor of Metalloproteinase-3 - metabolism; Up-Regulation
• ISSN: 1352-4585; 1477-0970
• DOI: 10.1191/135248506ms1300oa

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.