Little is known about the deposition and turnover of proteoglycans in liver fibrosis, despite their abundance in the extracellular matrix. Versican plays diverse roles in modulating cell behavior in other fibroproliferative diseases, but remains poorly described in the liver. Hepatic fibrosis was induced by carbon tetrachloride treatment of C57BL/6 mice over 4 weeks followed by recovery over a 28-day period. Primary mouse hepatic stellate cells (HSCs) were activated in culture and versican was transiently knocked down in human (LX2) and mouse HSCs. Expression of versican, A Disintegrinlike and Metalloproteinase with Thrombospondin-1 motifs (ADAMTS)-1, -4, -5, -8, -9, -15, and -20, and markers of fibrogenesis were studied using immunohistochemistry, real-time quantitative PCR, and western blotting. Immunohistochemistry showed increased expression of versican in cirrhotic human livers and the mouse model of fibrosis. Carbon tetrachloride treatment led to significant increases in versican expression and the proteoglycanases ADAMTS-5, -9, -15, and -20, alongside TNF-α, α-smooth muscle actin (α-SMA), collagen-1, and TGF-β expression. During recovery, expression of many of these genes returned to control levels. However, expression of ADAMTS-5, -8, -9, and -15 showed delayed increases in expression at 28 days of recovery, which corresponded with decreases in versican V0 and V1 cleavage products (G1-DPEAAE 1401 and G1-DPEAAE 441 ). Activation of primary HSCs in vitro significantly increased versican, α-SMA, and collagen-1 expression. Transient knockdown of versican in HSCs led to decreases in markers of fibrogenesis and reduced cell proliferation, without inducing apoptosis. Versican expression increases during HSC activation and liver fibrosis, and proteolytic processing occurs during the resolution of fibrosis. Knockdown studies in vitro suggest a possible role of versican in modulating hepatic fibrogenesis.

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Versican (VCAN) proteolysis and the accumulation of VCAN fragments occur in many developmental and disease processes, affecting extracellular matrix (ECM) structure and cell phenotype. Little is known about the significance of proteolysis and the roles of fragments, or how this ECM remodeling affects the microenvironment and phenotype of diseased cells. G1-DPEAAE fragments promote aspects of epithelial–mesenchymal transitioning in developing and diseased cells, resulting in cell migration. Enhanced proliferation and invasion of tumor and endothelial cells is directly associated with G1 domain deposition and G1-DPEAAE localization respectively. These tumorigenic and angiogenic roles could explain the disease exacerbating effect often associated with G1-containing fragments, however, the pathogenicity of G1 fragments depends entirely upon the context. Overall, VCAN fragments promote tumorigenesis and inflammation; however, the specific cleavage site, the extent of cleavage activity and the microenvironment in which cleavage occurs collectively determine how this pleiotropic molecule and its fragments influence cells.