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. 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) Liver fibrosis is a wound-healing response to chronic liver injuries, including viral infection,

alcohol consumption, and metabolic diseases.1 Persistent regeneration stimuli Dasatinib order lead to an excessive accumulation of extracellular matrix (ECM) and disorganized liver architecture. As the main cellular source of ECM, hepatic stellate cells (HSCs) play a critical role in hepatic fibrosis and, after injury, undergo an “activation” process that consists of the transition from find more quiescent vitamin A–rich cells in the healthy liver to proliferating, fibrogenic, and contractile myofibroblasts.2 HSCs also drive ECM remodeling by providing matrix metalloproteinases (MMPs)

and tissue inhibitors of MMPs (TIMPs). MMPs have been implicated in the breakdown of normal matrix during the early steps of fibrosis, facilitating its replacement by scar matrix, whereas an increase in the synthesis of TIMPs blocks collagenase activities in advanced stages of fibrosis.3 More recently, we and others have reported the altered expression of other metallopeptidases, including members of the A Disintegrin And Metalloprotease (ADAM) protein family and the related proteins with thrombospondin mombospondin motifs (ADAMTSs), thereby leading to a more complex view of metalloprotease involvement in fibrosis.4-8 ADAMs constitute a family of cell-surface proteins involved in ectodomain shedding, cell adhesion, and cell signaling. ADAMs share a multidomain organization that includes metalloprotease, disintegrin,

cystein, transmembrane, and cytoplasmic domains9 and have been implicated in diverse biological processes, including spermatogenesis/fertilization, neurogenesis, inflammatory responses, and cancer.10 ADAMTSs, and their Arachidonate 15-lipoxygenase related forms, ADAMTSLs (ADAMTS-like molecules that lack proteolytic activity), are characterized by an ancillary domain containing one or more thrombospondin type 1 repeat.11 Unlike mammalian ADAMs that are, with the exception of variant forms of ADAM-12 and -28, transmembrane proteins, ADAMTSs are secreted molecules that associate with ECM components. ADAMTS proteases are involved in the maturation of procollagen and von Willebrand factor, as well as in ECM proteolysis relating to morphogenesis, angiogenesis, fertility, arthritis, and cancer. Metallopeptidases are the most diverse class of human proteases. Their expression is altered in various pathologies12, 13 and they constitute promising therapeutic targets.