Expression of specific matrix metalloproteinases in inflammatory myopathies.
The family of matrix metalloproteinases (MMPs) comprises endopeptidases that are capable of degrading all extracellular matrix components. Given these actions, it is conceivable that MMPs may play a pathogenic role in inflammatory myopathies. These immune-mediated disorders are characterized by the invasion of mononuclear phagocytes and T lymphocytes and the loss of muscle fibres. We examined whether specific MMPs and their natural inhibitors (tissue inhibitors of metalloproteinases; TIMPs) are expressed in muscle during acute inflammatory attacks by studying muscle biopsies obtained from patients diagnosed as having polymyositis, dermatomyositis, sporadic inclusion body myositis and, for comparison, from cases of various muscular dystrophies. Quantitative polymerase chain reaction analysis revealed significantly elevated mRNA expression of interstitial collagenase (MMP-1) and gelatinase B (MMP-9) in polymyositis and dermatomyositis and to a lesser extent in inclusion body myositis, whereas the level of expression of TIMPs remained unchanged in comparison with controls. Increased mRNA levels were associated with enhanced enzyme expression, as determined by immunoblotting, gelatin zymography and in situ zymography. Immunohistochemically, MMP-1 could be localized around the sarcolemma of diseased muscle fibres and to cells resembling fibroblasts, whereas MMP-9 seemed to be expressed primarily by invading T lymphocytes. Raised levels of MMPs could not be detected in the sera of affected patients, emphasizing the crucial action of MMPs in the inflamed muscle. Our results imply a pathogenic role for specific MMPs in the genesis of inflammatory myopathies, and open new strategies for therapeutic intervention.
Kieseier
B C
BC
Department of Neurology, Karl Franzens University, Graz, Austria. bc.kieseier@kfunigraz.ac.at
Schneider
C
C
Clements
J M
JM
Gearing
A J
AJ
Gold
R
R
Toyka
K V
KV
Hartung
H P
HP
D000328:Adult; D000368:Aged; D002648:Child; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D020782:Matrix Metalloproteinases / Q000096:biosynthesis* / Q000235:genetics; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism; D009136:Muscular Dystrophies / Q000378:metabolism; D009220:Myositis / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000378:metabolism; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D019717:Tissue Inhibitor of Metalloproteinase-3; D019716:Tissue Inhibitor of Metalloproteinase-2; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1