Elevated plasma levels of tissue inhibitors of metalloproteinase-1 and their overexpression in muscle in human and mouse muscular dystrophy.
To investigate the role of tissue inhibitors of metalloproteinases (TIMPs) in muscular dystrophy, we examined the expression of TIMP-1 using plasma and biopsied muscle from patients with various muscular dystrophies by ELISA, immunohistochemistry, and Western blot analysis. TIMP-1 immunolocalization was also studied in mouse models of muscular dystrophy. Plasma TIMP-1 was elevated and correlated with TGF-β1 in Duchenne muscular dystrophy (DMD) and congenital muscular dystrophy (CMD), but not in Becker muscular dystrophy. In dystrophic human muscles, TIMP-1 was immunopositive in the regenerating and non-regenerating muscle fibers, and interstitial cells that consist of activated fibroblasts and macrophages. TIMP-1 immunoreactivity was also closely associated with TGF-β1. Western blot analysis showed elevated TIMP-1 protein in muscles in DMD. The semiquantitative analysis of TIMP-1 staining intensity and tissue fibrosis showed that TIMP-1 immunoreactivity is closely associated with the extent of tissue fibrosis in human and mouse dystrophic muscles. In conclusion, the present study implied that the TGF-β1-TIMP-1 pathway is activated in dystrophic muscles and the overexpression of TIMP-1 may result in increased deposition of extracellular matrix leading to tissue fibrosis.
Sun
Guilian
G
Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan; Department of Pediatrics, The First Affiliated Hospital, China Medical University, Shenyang 110001, China.
Haginoya
Kazuhiro
K
Chiba
Yoko
Y
Uematsu
Mitsugu
M
Hino-Fukuyo
Naomi
N
Tanaka
Soichiro
S
Onuma
Akira
A
Iinuma
Kazuie
K
Tsuchiya
Shigeru
S
D000293:Adolescent; D000818:Animals; D002648:Child; D002675:Child, Preschool; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000378:metabolism* / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism*; D009136:Muscular Dystrophies / Q000145:classification / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D013223:Statistics as Topic; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
D019715:Tissue Inhibitor of Metalloproteinase-1; D053773:Transforming Growth Factor beta1