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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

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. 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE24667 | GEO | 2012/01/05

SECONDARY ACCESSION(S): PRJNA132541

REPOSITORIES: GEO

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Project description: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. Total RNA from 32 patients with hepatic fibrosis associated with hepatitis C virus (HCV) infection (n=15) or alcohol abuse (n=17) versus a common pooled control liver sample, inverting the cy3 and cy5 labelling for each sample.

Project description:Venkatraman2012 - Interplay between PLS and TSP1 in TGF-β1 activation The interplay between PLS (Plasmin) and TSP1 (Thrombospondin-1) in TGF-β1 (Transforming growth factor-β1)is shown using mathematical modelling and in vitro experimentents. This model is described in the article: Plasmin triggers a switch-like decrease in thrombospondin-dependent activation of TGF-β1. Venkatraman L, Chia SM, Narmada BC, White JK, Bhowmick SS, Forbes Dewey C Jr, So PT, Tucker-Kellogg L, Yu H. Biophys J. 2012 Sep 5;103(5):1060-8. Abstract: Transforming growth factor-β1 (TGF-β1) is a potent regulator of extracellular matrix production, wound healing, differentiation, and immune response, and is implicated in the progression of fibrotic diseases and cancer. Extracellular activation of TGF-β1 from its latent form provides spatiotemporal control over TGF-β1 signaling, but the current understanding of TGF-β1 activation does not emphasize cross talk between activators. Plasmin (PLS) and thrombospondin-1 (TSP1) have been studied individually as activators of TGF-β1, and in this work we used a systems-level approach with mathematical modeling and in vitro experiments to study the interplay between PLS and TSP1 in TGF-β1 activation. Simulations and steady-state analysis predicted a switch-like bistable transition between two levels of active TGF-β1, with an inverse correlation between PLS and TSP1. In particular, the model predicted that increasing PLS breaks a TSP1-TGF-β1 positive feedback loop and causes an unexpected net decrease in TGF-β1 activation. To test these predictions in vitro, we treated rat hepatocytes and hepatic stellate cells with PLS, which caused proteolytic cleavage of TSP1 and decreased activation of TGF-β1. The TGF-β1 activation levels showed a cooperative dose response, and a test of hysteresis in the cocultured cells validated that TGF-β1 activation is bistable. We conclude that switch-like behavior arises from natural competition between two distinct modes of TGF-β1 activation: a TSP1-mediated mode of high activation and a PLS-mediated mode of low activation. This switch suggests an explanation for the unexpected effects of the plasminogen activation system on TGF-β1 in fibrotic diseases in vivo, as well as novel prognostic and therapeutic approaches for diseases with TGF-β dysregulation. This model is hosted on BioModels Database and identified by: MODEL1303130000 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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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

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