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. (HEPATOLOGY 2011)

ADAMTS1 protease is required for a balanced immune cell repertoire and tumour inflammatory response

“…At this point, we should recall the original cloning of mouse Adamts1 in a cachexia model 6 , a phenomena with a recognized inflammatory component. However, no further studies have focused exactly on this context, excluding a few references that revealed its genetic regulation by a variety of cytokines 6,49 .…”

Cytokine Production and Signaling in Stellate Cells

“…While integrins, fibrinogen, and urokinase-type plasminogen activator are factors involved in TGF-β activation [46][47][48], TGF-β may be inactivated by the proteoglycan decorin [49]. In HSCs, ADAMTS1 induces TGF-β activation through an interaction of the latency-associated peptide with TGF-β, and its downregulation decreases the release of TGF-β [50].…”

Biological Significance of Local TGF-β Activation in Liver Diseases

“…A number of proteases, including plasmin, matrix metalloproteinase (MMP)-2/9, and a disintegrin and metalloproteinase with TSP motifs 1 (ADAMTS1), have been identified as latent TGF-β activators in vitro (Lyons et al, 1988; Sato and Rifkin, 1989; Yu and Stamenkovic, 2000; Bourd-Boittin et al, 2011). Plasmin and MMP-2/9 belong to the serine protease and metalloproteinase families, respectively.…”

“…A very recent study using a proteinase-related gene sample identified ADAMTS1 as an upregulated fibrosis-related protease in human liver fibrosis (Bourd-Boittin et al, 2011). ADAMTSs are characterized by an ancillary domain containing one or more TSP type 1 repeats (Apte, 2009).…”