title: Protease profiling of liver fibrosis reveals the ADAM metallopeptidase with thrombospondin type 1 motif, 1 as a central activator of transforming growth factor beta.
abstract: 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.
  
  
  CONCLUSIONS
  Our results indicate that up-regulation of ADAMTS1 in HSCs constitutes a new mechanism for control of TGF-β activation in chronic liver disease.
authors.affiliation: Institut de Recherche en Santé, Environnement et Travail EA4427 SeRAIC, Université de Rennes 1, IFR14, Rennes, France.
authors.forename: Katia
authors.initials: K
authors.lastname: Bourd-Boittin
authors.forename: Dominique
authors.initials: D
authors.lastname: Bonnier
authors.forename: Anthony
authors.initials: A
authors.lastname: Leyme
authors.forename: Bernard
authors.initials: B
authors.lastname: Mari
authors.forename: Pierre
authors.initials: P
authors.lastname: Tuffery
authors.forename: Michel
authors.initials: M
authors.lastname: Samson
authors.forename: Frédéric
authors.initials: F
authors.lastname: Ezan
authors.forename: Georges
authors.initials: G
authors.lastname: Baffet
authors.forename: Nathalie
authors.initials: N
authors.lastname: Theret
mesh_terms: D051722:ADAM Proteins / Q000502:physiology*; D000071097:ADAMTS1 Protein; D000368:Aged; D020816:Amino Acid Motifs / Q000502:physiology; D000818:Animals; D002251:Carbon Tetrachloride; D024042:Collagen Type I / Q000096:biosynthesis; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D020869:Gene Expression Profiling; D055166:Hepatic Stellate Cells / Q000502:physiology; D006801:Humans; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008875:Middle Aged; D010455:Peptides / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D024042:Collagen Type I; D010455:Peptides; D011498:Protein Precursors; D016212:Transforming Growth Factor beta; C472416:latency-associated propeptide, TGF-beta; D002251:Carbon Tetrachloride; D051722:ADAM Proteins; D000071097:ADAMTS1 Protein; C103859:ADAMTS1 protein, human