Ej. Williams et al., Relaxin inhibits effective collagen deposition by cultured hepatic stellate cells and decreases rat liver fibrosis in vivo, GUT, 49(4), 2001, pp. 577-583
Background-Following liver injury, hepatic stellate cells (HSC) transform i
nto myofibroblast-like cells (activation) and are the major source of type
I collagen and the potent collagenase inhibitors tissue inhibitors of metal
loproteinases 1 and 2 (TIMP-1 and TIMP-2) in the fibrotic liver. The reprod
uctive hormone relaxin has been reported to reduce collagen and TIMP-1 expr
ession by dermal and lung fibroblasts and thus has potential antifibrotic a
ctivity in liver fibrosis.
Aims-To determine the effects of relaxin on activated HSC.
Methods-Following isolation, HSC were activated by culture on plastic and e
xposed to relaxin (1-100 ng/ml). Collagen deposition was determined by Siri
us red dye binding and radiolabelled proline incorporation. Matrix metallop
roteinase (MMP) and TIMP expression were assessed by zymography and norther
n analysis. Transforming growth factor beta1 (TGF-beta1) mRNA and protein l
evels were quantified by northern analysis and ELISA, respectively.
Results-Exposure of activated HSC to relaxin resulted in a concentration de
pendent decrease in both collagen synthesis and deposition. There was a par
allel decrease in TIMP- 1 and TIMP-2 secretion into the HSC conditioned med
ia but no change in gelatinase expression was observed. Northern analysis d
emonstrated that primary HSC, continuously exposed to relaxin, had decrease
d TIMP-1 mRNA expression but unaltered type I collagen, collagenase (MMP-13
), alpha smooth muscle actin, and TGF-beta1 mRNA expression.
Conclusion-These data demonstrate that relaxin modulates effective collagen
deposition by HSC, at least in part, due to changes in the pattern of matr
ix degradation.