title: Mutation in collagen-1 that confers resistance to the action of collagenase results in failure of recovery from CCl4-induced liver fibrosis, persistence of activated hepatic stellate cells, and diminished hepatocyte regeneration.
abstract: Collagen-I, which predominates in the neomatrix of fibrotic liver, regulates hepatocyte and hepatic stellate cell (HSC) phenotypes. Recovery from liver fibrosis is accompanied by hepatocyte regeneration, matrix degradation, and HSC apoptosis. Using mice bearing a mutated collagen-I gene (r/r mice), which confers resistance to collagenase degradation, we have investigated the hypothesis that collagen-I degradation is critical to HSC apoptosis and hepatocyte regeneration during recovery from liver fibrosis. During a 28-day recovery period after 8 wk of CCl4 treatment, wild-type (WT) livers had significantly (43%) decreased hydroxyproline (OHP) content. In r/r livers, however, OHP content remained elevated at peak fibrosis levels. Expressed markers of activated HSC (alpha-smooth muscle actin, collagen-I), elevated at peak fibrosis, dropped to control levels in WT livers after 28 days but remained raised in the r/r livers. Moreover, relative to WT livers, r/r livers had significantly reduced stellate cell apoptosis and hepatocyte regeneration during the recovery period. Using extracted collagen-I from each genotype as culture substrata, relative to r/r, we show that WT collagen-I promotes hepatocyte proliferation via stimulation of integrin alpha(v)beta3. Failure to degrade collagen-I critically impairs HSC apoptosis and may prevent the effective restoration of hepatocyte mass in liver fibrosis.
authors.affiliation: Liver Research Group and Department of Histopathology, Infection, Inflammation and Repair, South Lab and Path Block, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK.
authors.forename: Razao
authors.initials: R
authors.lastname: Issa
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Zhou
authors.forename: Nathan
authors.initials: N
authors.lastname: Trim
authors.forename: Harry
authors.initials: H
authors.lastname: Millward-Sadler
authors.forename: Stephen
authors.initials: S
authors.lastname: Krane
authors.forename: Christopher
authors.initials: C
authors.lastname: Benyon
authors.forename: John
authors.initials: J
authors.lastname: Iredale
mesh_terms: D000818:Animals; D017209:Apoptosis; D002251:Carbon Tetrachloride; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D017364:Collagenases / Q000378:metabolism; D022781:Hepatocytes / Q000502:physiology; D007700:Kinetics; D008099:Liver / Q000166:cytology* / Q000378:metabolism; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D008115:Liver Regeneration; D051379:Mice; D008954:Models, Biological; D009154:Mutation; D012333:RNA, Messenger / Q000096:biosynthesis
chemical_list: D024042:Collagen Type I; D012333:RNA, Messenger; D002251:Carbon Tetrachloride; D017364:Collagenases