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 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.
von Moers
Arpad
A
Department of Neuropediatrics, Charité, University Medical Center Berlin, Augustenburger Platz 1, 13353, Berlin, Germany. arpad.von_moers@charite.de
Zwirner
Angelika
A
Reinhold
Anke
A
Brückmann
Olaf
O
van Landeghem
Frank
F
Stoltenburg-Didinger
Gisela
G
Schuppan
Detlef
D
Herbst
Herrman
H
Schuelke
Markus
M
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004586:Electrophoresis / Q000379:methods; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D009132:Muscles / Q000187:drug effects / Q000201:enzymology; D020388:Muscular Dystrophy, Duchenne / Q000201:enzymology* / Q000235:genetics; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D016372:RNA, Antisense / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D018709:Statistics, Nonparametric; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology; D014746:Vimentin / Q000378:metabolism
D019408:Platelet Endothelial Cell Adhesion Molecule-1; D016372:RNA, Antisense; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D014746:Vimentin; D019716:Tissue Inhibitor of Metalloproteinase-2