title: Versican: a novel modulator of hepatic fibrosis.
abstract: 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 Disintegrin-like 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.
authors.affiliation: Northern Medical Program, University of Northern British Columbia, Dr. Donald Rix Northern Health Sciences Centre, Prince George, BC, Canada.
authors.forename: Terence N
authors.initials: TN
authors.lastname: Bukong
authors.affiliation: Northern Medical Program, University of Northern British Columbia, Dr. Donald Rix Northern Health Sciences Centre, Prince George, BC, Canada.|Department of Cellular and Physiological Sciences, Faculty of Medicine, University of British Columbia, BC, Canada.
authors.forename: Sean B
authors.initials: SB
authors.lastname: Maurice
authors.affiliation: Northern Medical Program, University of Northern British Columbia, Dr. Donald Rix Northern Health Sciences Centre, Prince George, BC, Canada.|Faculty of Medicine, University of British Columbia, BC, Canada.
authors.forename: Barinder
authors.initials: B
authors.lastname: Chahal
authors.affiliation: Department of Pathology and Laboratory Medicine, Faculty of Medicine, University of British Columbia, BC, Canada.
authors.forename: David F
authors.initials: DF
authors.lastname: Schaeffer
authors.affiliation: Northern Medical Program, University of Northern British Columbia, Dr. Donald Rix Northern Health Sciences Centre, Prince George, BC, Canada.|Faculty of Medicine, University of British Columbia, BC, Canada.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Winwood
mesh_terms: D051722:ADAM Proteins / Q000502:physiology; D000071096:ADAMTS Proteins; D000071097:ADAMTS1 Protein; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002470:Cell Survival; D005260:Female; D055166:Hepatic Stellate Cells / Q000378:metabolism; D006801:Humans; D008103:Liver Cirrhosis / Q000209:etiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D053675:Versicans / Q000502:physiology*
chemical_list: D053675:Versicans; D051722:ADAM Proteins; D000071096:ADAMTS Proteins; D000071097:ADAMTS1 Protein; C103859:ADAMTS1 protein, human; C500267:ADAMTS15 protein, human