Increased mRNA expression of tissue inhibitors of metalloproteinase-1 and -2 in Duchenne muscular dystrophy

In dystrophinopathies, disease severity is generally related to the extent of muscle fibrosis. To determine whether a decrease in matrix degradation contributes to the severe fibrosis seen in Duchenne muscular dystrophy (DMD), we quantified RNA transcript numbers for the fibrolytic matrix metallopro...

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Bibliographic Details
Published in:Acta neuropathologica 2005-04, Vol.109 (3), p.285-293
Main Authors: von Moers, Arpad, Zwirner, Angelika, Reinhold, Anke, Brückmann, Olaf, van Landeghem, Frank, Stoltenburg-Didinger, Gisela, Schuppan, Detlef, Herbst, Herrman, Schuelke, Markus
Format: Article
Language:English
Subjects:
Adolescent
Child
Child, Preschool
DNA Mutational Analysis
Electrophoresis - methods
Humans
Immunohistochemistry - methods
Male
Muscles - drug effects
Muscles - enzymology
Muscular Dystrophy, Duchenne - enzymology
Muscular Dystrophy, Duchenne - genetics
Platelet Endothelial Cell Adhesion Molecule-1 - metabolism
Reverse Transcriptase Polymerase Chain Reaction - methods
RNA, Antisense - pharmacology
RNA, Messenger - metabolism
Statistics, Nonparametric
Tissue Inhibitor of Metalloproteinase-1 - genetics
Tissue Inhibitor of Metalloproteinase-1 - metabolism
Tissue Inhibitor of Metalloproteinase-2 - genetics
Tissue Inhibitor of Metalloproteinase-2 - metabolism
Up-Regulation - physiology
Vimentin - metabolism
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Summary:In dystrophinopathies, disease severity is generally related to the extent of muscle fibrosis. To determine whether a decrease in matrix degradation contributes to the severe fibrosis seen in Duchenne muscular dystrophy (DMD), we quantified RNA transcript numbers for the fibrolytic matrix metalloproteinases (MMP)-1 and -2 and their natural tissue inhibitors (TIMP)-1 and -2 in DMD muscle as well as in pathological and normal controls. In addition, we investigated gelatinase (MMP-2) enzyme activity by zymography. We found an up-regulation of TIMP-1, TIMP-2 and MMP-2 RNA in DMD muscle. Zymography revealed an increase in MMP-2 activity in DMD muscle homogenates, which was absent in pathological and normal controls. Therefore, besides enhanced fibrogenesis, a disturbance of matrix degradation may play a significant role in muscle fibrosis in DMD. TIMP-1 should be investigated further as a promising target for pharmacological intervention to prevent muscle fibrosis in DMD.
ISSN:0001-6322
1432-0533
DOI:10.1007/s00401-004-0941-0