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Protease profiling of liver fibrosis reveals the ADAM metallopeptidase with thrombospondin type 1 motif, 1 as a central activator of transforming growth factor beta
Author(s) -
BourdBoittin Katia,
Bonnier Dominique,
Leyme Anthony,
Mari Bernard,
Tuffery Pierre,
Samson Michel,
Ezan Frédéric,
Baffet Georges,
Theret Nathalie
Publication year - 2011
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.24598
Subject(s) - hepatic stellate cell , thrombospondin , metalloproteinase , transforming growth factor beta , fibrosis , chemistry , proteases , transforming growth factor , matrix metalloproteinase , thrombospondin 1 , adamts , microbiology and biotechnology , cancer research , protease , hepatic fibrosis , adamts13 , biology , immunology , biochemistry , endocrinology , medicine , enzyme , angiogenesis , platelet , thrombotic thrombocytopenic purpura
During chronic liver disease, tissue remodeling leads to dramatic changes and accumulation of matrix components. Matrix metalloproteases and their inhibitors have been involved in the regulation of matrix degradation. However, the role of other proteases remains incompletely defined. We undertook a gene‐expression screen of human liver fibrosis samples using a dedicated gene array selected for relevance to protease activities, identifying the ADAMTS1 (A Disintegrin And Metalloproteinase [ADAM] with thrombospondin type 1 motif, 1) gene as an important node of the protease network. Up‐regulation of ADAMTS1 in fibrosis was found to be associated with hepatic stellate cell (HSC) activation. ADAMTS1 is synthesized as 110‐kDa latent forms and is processed by HSCs to accumulate as 87‐kDa mature forms in fibrotic tissues. Structural evidence has suggested that the thrombospondin motif‐containing domain from ADAMTS1 may be involved in interactions with, and activation of, the major fibrogenic cytokine, transforming growth factor beta (TGF‐β). Indeed, we observed direct interactions between ADAMTS1 and latency‐associated peptide‐TGF‐β (LAP‐TGF‐β). ADAMTS1 induces TGF‐β activation through the interaction of the ADAMTS1 KTFR peptide with the LAP‐TGF‐β LKSL peptide. Down‐regulation of ADAMTS1 in HSCs decreases the release of TGF‐β competent for transcriptional activation, and KTFR competitor peptides directed against ADAMTS1 block the HSC‐mediated release of active TGF‐β. Using a mouse liver fibrosis model, we show that carbon tetrachloride treatment induces ADAMTS1 expression in parallel to that of type I collagen. Importantly, concurrent injection of the KTFR peptide prevents liver damage. Conclusion: Our results indicate that up‐regulation of ADAMTS1 in HSCs constitutes a new mechanism for control of TGF‐β activation in chronic liver disease. (H EPATOLOGY 2011)