Expression of decorin, transforming growth factor-beta 1, tissue inhibitor metalloproteinase 1 and 2, and type IV collagenases in chronic hepatitis.
Decorin is a small extracellular matrix proteoglycan. It binds and modulates transforming growth factor (TGF)-beta 1 action, the major stimulator of fibrogenesis. Its role in the pathogenesis of human liver cirrhosis is unknown. Therefore, we studied the relationship of the 2 proteins in normal human liver and in 43 chronic hepatitis and liver cirrhosis specimens. To understand the mechanism that maintains matrix deposition in stage IV hepatitis, we studied expression of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2, as well as the activities of type IV collagenases. Gene expression was analyzed on messenger RNA and protein level by morphologic and biochemical approaches. Decorin proved to be an early marker of fibrogenesis, and its deposition increased parallel to that of TGF-beta 1 and to inflammatory activity. Liver fibrosis progressed despite high temporospatial expression of decorin with TGF-beta 1. Neither decorin nor TGF-beta 1 protein deposition increased further in cirrhosis with low inflammatory activity, suggesting that impaired extracellular matrix catabolism rather than active production plays a role in this stage. This possibility was supported by high message levels of metalloproteinase inhibitors, no 72-kd collagenase activities, and low 92-kd collagenase activities.
Dudás
J
J
First Department of Pathology and Experimental Cancer Research, Semmelweis University Budapest, Budapest, Hungary.
Kovalszky
I
I
Gallai
M
M
Nagy
J O
JO
Schaff
Z
Z
Knittel
T
T
Mehde
M
M
Neubauer
K
K
Szalay
F
F
Ramadori
G
G
D015152:Blotting, Northern; D017364:Collagenases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers / Q000737:chemistry; D058575:Decorin; D016326:Extracellular Matrix Proteins; D005260:Female; D006521:Hepatitis, Chronic / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D008099:Liver / Q000378:metabolism; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D011509:Proteoglycans / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1
C546878:DCN protein, human; D017931:DNA Primers; D058575:Decorin; D016326:Extracellular Matrix Proteins; D011509:Proteoglycans; D012333:RNA, Messenger; C508960:TGFB1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D019716:Tissue Inhibitor of Metalloproteinase-2; D017364:Collagenases