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: Tung-Ming Leung, Xiaodong Wang, Naoto Kitamura, Maria I Fiel, Natalia Nieto
• Journal: Laboratory investigation; a journal of technical methods and pathology (Lab Invest) Vol. 93 Issue 10 Pg. 1082-9 (Oct 2013) ISSN: 1530-0307 [Electronic] United States
• PMID: 23999249 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Actins
• Biomarkers
• Collagen Type I
• Spp1 protein, mouse
• Timp1 protein, mouse
• Tissue Inhibitor of Metalloproteinase-1
• alpha-smooth muscle actin, mouse
• Thioacetamide
• Osteopontin

Topics

• Actins (biosynthesis, metabolism)
• Animals
• Biomarkers (metabolism)
• Collagen Type I (metabolism)
• Crosses, Genetic
• Disease Models, Animal
• Extracellular Matrix (immunology, metabolism, pathology)
• Hepatic Stellate Cells (immunology, metabolism, pathology)
• Liver (immunology, pathology, physiology)
• Liver Cirrhosis (immunology, metabolism, pathology, physiopathology)
• Liver Regeneration
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Necrosis
• Osteopontin (genetics, metabolism)
• Protein Stability
• Thioacetamide
• Tissue Inhibitor of Metalloproteinase-1 (biosynthesis, metabolism)