title: Osteopontin delays resolution of liver fibrosis.
abstract: To date, considerable progress has been made both in the mechanisms driving liver fibrosis and in the prevention of disease progression. Resolution of liver fibrosis is an emerging field in hepatology; yet, the mediators involved remain elusive. Earlier work from our laboratory demonstrated that the matricellular cytokine osteopontin (OPN) is pro-fibrogenic by promoting hepatic stellate cell (HSC) activation and extracellular matrix (ECM) deposition in vitro and in vivo and specifically by governing fibrillar collagen-I expression, the key pro-fibrogenic protein. Here we hypothesized that OPN could also delay the resolution of liver fibrosis by sustaining collagen-I synthesis or by preventing its degradation. To demonstrate this, wild-type (WT) and OPN-knockout (Opn(-/-)) mice were administered thioacetamide (TAA) in the drinking water for 4 months. Half of the mice were killed at 4 months to assess the extent of fibrosis at the peak of injury, and the rest of the mice were killed 2 months after TAA withdrawal to determine the rate of fibrosis resolution. Following TAA cessation, livers from Opn(-/-) mice showed no centrilobular and parenchymal necrosis along with faster ECM remodeling than WT mice. The latter was quantified by less fibrillar collagen-I immunostaining. Western blot analysis demonstrated a significant decrease in fibrillar collagen-I and in tissue inhibitor of metalloproteinase-1 (TIMP-1) in Opn(-/-) mice undergoing fibrosis resolution compared with WT mice. In conclusion, these results suggest that OPN delays liver fibrosis resolution due to sustained fibrillar collagen-I deposition; hence, inhibiting OPN could be an effective therapeutic strategy for resolving liver fibrosis.
authors.affiliation: Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: Tung-Ming
authors.initials: TM
authors.lastname: Leung
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Wang
authors.forename: Naoto
authors.initials: N
authors.lastname: Kitamura
authors.forename: Maria I
authors.initials: MI
authors.lastname: Fiel
authors.forename: Natalia
authors.initials: N
authors.lastname: Nieto
mesh_terms: D000199:Actins / Q000096:biosynthesis / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D024042:Collagen Type I / Q000378:metabolism; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D055166:Hepatic Stellate Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000276:immunology / Q000473:pathology / Q000502:physiology*; D008103:Liver Cirrhosis / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008115:Liver Regeneration; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009336:Necrosis; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D013853:Thioacetamide; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis / Q000378:metabolism
chemical_list: D000199:Actins; D015415:Biomarkers; D024042:Collagen Type I; C506896:Spp1 protein, mouse; C560825:Timp1 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1; C544013:alpha-smooth muscle actin, mouse; D013853:Thioacetamide; D053495:Osteopontin