Protease profiling of liver fibrosis reveals the adam metallopeptidase with thrombospondin type 1 motif, 1 as a central activator of TGF-β - Inria - Institut national de recherche en sciences et technologies du numérique Accéder directement au contenu
Article Dans Une Revue Hepatology Année : 2011

Protease profiling of liver fibrosis reveals the adam metallopeptidase with thrombospondin type 1 motif, 1 as a central activator of TGF-β

Résumé

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 (ADAM metallopeptidase with thrombospondin type 1 motif, 1) gene as an important node of the protease network. Upregulation of ADAMTS1 in fibrosis was found to be associated with hepatic stellate cell (HSC) activation. ADAMTS1 is synthesized as 110-kDa latent forms and processed by HSCs to accumulate as 87-kDa mature forms in fibrotic tissues. Structural evidence suggested that the thrombospondin motif-containing domain from ADAMTS1 may be involved in interactions with, and activation of, the major fibrogenic cytokine, 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 HSC-mediated release of active TGF-β. Using a mouse liver fibrosis model, we show that CCl(4) 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. (HEPATOLOGY 2011.).

Dates et versions

hal-00626026 , version 1 (23-09-2011)

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Citer

Katia Bourd-Boittin, Dominique Bonnier, Anthony Leyme, Bernard Mari, Pierre Tuffery, et al.. Protease profiling of liver fibrosis reveals the adam metallopeptidase with thrombospondin type 1 motif, 1 as a central activator of TGF-β. Hepatology, 2011, 54 (6), pp.2173-2184. ⟨10.1002/hep.24598⟩. ⟨hal-00626026⟩
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