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From the Neuromuscular Disease Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.
Address correspondence and reprint requests to Dr. Marinos C. Dalakas, Chief Neuromuscular Disease Section, National Institute of Neurological Disorders and Stroke, National Institute of Health, Building 10, Room 4N248, 10 Center DR MSC 1382, Bethesda, MD 20892-1382; e-mail: dalakas{at}helix.nih.gov
OBJECTIVE: To investigate the role of matrix metalloproteinases (MMPs) in the pathogenesis of inflammatory myopathies and the amyloid formation in sporadic inclusion body myositis (s-IBM).
BACKGROUND: MMPs comprise a family of calcium-dependent zinc endoproteinases induced by cytokines and secreted by inflammatory cells. They enhance T-cell migration or adhesion and degrade components of the extracellular matrix proteins. Some MMPs also have been implicated in the formation of ß-amyloid.
METHODS: We examined the expression of MMPs with single and double immunocytochemistry using antibodies against MMP-2, MMP-3, MMP-7, MMP-9, major histocompatibility complex (MHC) class I, CD8+ cells, macrophage, and ß-amyloid precursor protein (ß-APP) on serial muscle biopsy sections from patients with s-IBM, polymyositis (PM), dermatomyositis (DM), and disease control specimens. The enzyme activity of MMPs was measured by gelatin substrate zymography.
RESULTS: Only the gelatinases, MMP-9 and MMP-2, were expressed in the muscle. In s-IBM and PM, but not the control specimens, MMP-9 and MMP-2 immunostained the non-necrotic and MHC class-I-expressing muscle fibers, and MMP-9, but not MMP-2, immunostained the autoinvasive CD8+ cytotoxic T cells. Zymography in muscle homogenates confirmed the increased MMP-2 and MMP-9 enzymatic activity. MMP-2, but not MMP-9, immunostained the rimmed vacuoles in s-IBM and colocalized with ß-APP, suggesting a possible involvement with the amyloid deposits.
CONCLUSIONS: Because collagen IV is prominent on the muscle membrane, the overexpression of matrix metalloproteinases (MMPs) 2 and 9 on the non-necrotic muscle fibers in polymyositis (PM) and sporadic inclusion body myositis (s-IBM) may facilitate lymphocyte adhesion and enhance T-cell-mediated cytotoxicity by degrading extracellular matrix proteins. The findings may have practical implications in considering therapeutic trials with MMP inhibitors in patients with PM and s-IBM.
Key words: Matrix metalloproteinases 2 and 9—Inflammatory myopathies—ß-amyloid precursor protein
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