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.
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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)
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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
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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)
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