Ablation of the decorin gene enhances experimental hepatic fibrosis and impairs hepatic healing in mice.
Accumulation of connective tissue is a typical feature of chronic liver diseases. Decorin, a small leucine-rich proteoglycan, regulates collagen fibrillogenesis during development, and by directly blocking the bioactivity of transforming growth factor-β1 (TGFβ1), it exerts a protective effect against fibrosis. However, no in vivo investigations on the role of decorin in liver have been performed before. In this study we used decorin-null (Dcn-/-) mice to establish the role of decorin in experimental liver fibrosis and repair. Not only the extent of experimentally induced liver fibrosis was more severe in Dcn-/- animals, but also the healing process was significantly delayed vis-à-vis wild-type mice. Collagen I, III, and IV mRNA levels in Dcn-/- livers were higher than those of wild-type livers only in the first 2 months, but no difference was observed after 4 months of fibrosis induction, suggesting that the elevation of these proteins reflects a specific impairment of their degradation. Gelatinase assays confirmed this hypothesis as we found decreased MMP-2 and MMP-9 activity and higher expression of TIMP-1 and PAI-1 mRNA in Dcn-/- livers. In contrast, at the end of the recovery phase increased production rather than impaired degradation was found to be responsible for the excessive connective tissue deposition in livers of Dcn-/- mice. Higher expression of TGFβ1-inducible early responsive gene in decorin-null livers indicated enhanced bioactivity of TGFβ1 known to upregulate TIMP-1 and PAI-1 as well. Moreover, two main axes of TGFβ1-evoked signaling pathways were affected by decorin deficiency, namely the Erk1/2 and Smad3 were activated in Dcn-/- samples, whereas no significant difference in phospho-Smad2 was observed between mice with different genotypes. Collectively, our results indicate that the lack of decorin favors the development of hepatic fibrosis and attenuates its subsequent healing process at least in part by affecting the bioactivity of TGFβ1.
1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
Kornélia
K
Baghy
Katalin
K
Dezso
Viktória
V
László
Alexandra
A
Fullár
Bálint
B
Péterfia
Sándor
S
Paku
Péter
P
Nagy
Zsuzsa
Z
Schaff
Renato V
RV
Iozzo
Ilona
I
Kovalszky
D000818:Animals; D002460:Cell Line; D003238:Connective Tissue / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D058575:Decorin / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D053505:Matrix Metalloproteinases, Secreted / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D011347:Procollagen / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000187:drug effects; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
D058575:Decorin; D017395:Plasminogen Activator Inhibitor 1; D011347:Procollagen; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D053773:Transforming Growth Factor beta1; D053505:Matrix Metalloproteinases, Secreted