The role of decorin in liver fibrogenesis

Introduction: Accumulation of connective tissue is a typical feature of chronic liver diseases. TGF-β1 is one of the major stimulators of fibrogenesis; therefore, its neutralization is a principal aim in antifibrotic research. Decorin, a small ECM proteoglycan, is capable of regulating connective tissue proliferation by blocking the maturation of collagen fibrils, and by inhibiting TGF-β1. To better understand the role of decorin in liver fibrogenesis, an animal model was created.

Methods: Four mouse strain were used with different genetic background. Wild type, decorin KO (dec-/-), TGF-β1 transgenic mice overexpressing TGF-β1 in their liver (TGF-β1+) and double transgenic animals (dec-/-/TGF-β1+). These genetic modifications were expected to alter the response to chronic liver injury. Cirrhosis has been induced by thioacetamide (TA). The process of fibrogenesis was analyzed by fluorescence immunostaining, morphometry, zymography and real time RT-PCR.

Results: After administrating TA for 1, 2, 3, 4, 7 months, the severity of cirrhosis increased in the order Wt, dec-/-, TGF-β1+, dec-/-/TGF-β1+. Changes in collagen I, III, IV mRNA levels not went parallel with the quantity of the corresponding proteins. Presumably, the amount of these proteins is influenced by other factors, such as degradation, as well. This presumption was confirmed by gelatinase assay, showing different levels of MMP-2 and MMP-9 activities in cirrhotic livers of dec-/- and TGF-β1+ mice.

Conclusion: Our mouse strains responded differently to the treatment, depending on their levels of decorin and TGF-β1 expression. The lack of decorin alone promotes the development of fibrosis, and the extent of fibrosis is higher in the dec-/-/TGF-β1+ mice. These results indicate that decorin plays an important role in liver fibrogenesis.