| Abstrak/Abstract |
Background and Aims: Serum osteoprotegerin (OPG) has clinically
been associated with liver fibrosis and has been shown to increase diagnostic accuracy. However, the source and role of OPG is unknown and it is also not clear whether OPG expression responds to spontaneous or drug-induced resolution of fibrosis. Therefore, we aimed to evaluate the expression and biological activities of OPG in fibrotic human and mouse livers and to study its expression in relation to treatment-induced and spontaneous resolution.
Methods: Healthy and cirrhotic human liver tissue, liver tissue of
healthy mice and mice with CCl4-induced liver fibrosis with or
without treatment, murine precision-cut liver slices and 3T3
fibroblasts were analyzed by immunohistochemical staining, ELISA, and real time qPCR.
Results: Hepatic OPG levels were significantly higher in human
cirrhotic livers and CCl4-induced fibrotic mouse livers compared to healthy livers. Immunohistochemistry confirmed higher hepatic OPG expression in fibrotic tissue and showed localization of OPG in the cirrhotic collagenous bands co-localizing with myofibroblasts (?-smooth muscle actin-positive cells). Experiments with mouse precision-cut liver slices confirmed that liver tissue produces OPG, in particular after stimulationwith transforming growth factor-? (TGF?).
Stimulation of 3T3 fibroblasts with TGF? confirmed fibroblasts as
one of the main sources of OPG. Moreover, OPG itself stimulated
expressions of collagen-1?1, heat shock protein 47, plasminogen
activator inhibitor 1, fibronectin type 2, and importantly transforming growth factor-?, but not ?-smooth muscle actin in these liver slices. In vivo, cessation of CCl4 administration or treatment with interferon gamma (IFN?) in mice led to resolution of fibrosis, whichwas associated with significantly lower OPG expression in these livers. Likewise, IFN? significantly inhibited OPG production in mouseliver slices stimulated with TGF?.Conclusions: In conclusion, liver fibrosis is accompanied byincreased production of OPG in liver by (myo)fibroblasts, in particularin response toTGF?. OPG itself appears to be profibrotic. Spontaneousor drug (IFN?)-induced resolution of fibrosis is accompanied withlower expression of OPG and therefore OPG may be a novel drugtarget and/or biomarker for liver fibrosis. |
