Expression of matrix metalloproteinases in the muscle of patients with inflammatory myopathies

Neurology. 2000 Jan 11;54(1):65-71. doi: 10.1212/wnl.54.1.65.

Abstract

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 beta-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 beta-amyloid precursor protein (beta-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 beta-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.

MeSH terms

  • Amyloid beta-Protein Precursor / metabolism
  • CD8-Positive T-Lymphocytes / enzymology
  • Dermatomyositis / enzymology*
  • Dermatomyositis / metabolism
  • Dermatomyositis / pathology
  • Histocompatibility Antigens Class I / metabolism
  • Humans
  • Immunohistochemistry
  • Matrix Metalloproteinase 2 / metabolism*
  • Matrix Metalloproteinase 9 / metabolism*
  • Muscle Fibers, Skeletal / metabolism
  • Muscle, Skeletal / enzymology*
  • Muscle, Skeletal / pathology
  • Myositis, Inclusion Body / enzymology*
  • Myositis, Inclusion Body / metabolism
  • Myositis, Inclusion Body / pathology
  • Polymyositis / enzymology*
  • Polymyositis / metabolism
  • Polymyositis / pathology

Substances

  • Amyloid beta-Protein Precursor
  • Histocompatibility Antigens Class I
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9