期刊
LABORATORY INVESTIGATION
卷 93, 期 10, 页码 1082-1089出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/labinvest.2013.104
关键词
collagen-I; extracellular matrix; hepatic fibrosis; hepatic stellate cells; osteopontin
资金
- Keio University School of Medicine
- US Public Health Service Grants from the National Institute of Diabetes and Digestive and Kidney Diseases [5 R01 DK069286, 2 R56 DK069286, 3 R56 DK069286-06S1]
- US Public Health Service Grant from the National Institute on Alcohol Abuse and Alcoholism [U01 AA021887-01]
- US Public Health Service Grants from the National Institute on Alcohol Abuse and Alcoholism [5 P20 AA017067, 5 P20 AA017067-01S1, 5 P20 AA017067-03S1]
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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