Mice deficient in N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase exhibit enhanced liver fibrosis and delayed recovery from fibrosis in carbon tetrachloride-treated mice

Background: Chondroitin/dermatan sulfate (CS/DS) rich in N-acetylgalactosamine 4,6-bissulfate (Ga1NAc(4,6SO(4))) residues is present as decorin and/or biglycan in mouse liver, and Ga1NAc(4,6SO(4)) residues disappeared completely in N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase (Ga1NAc4S-6ST) knockout (KO) mice. The aim of this study was to investigate whether CS/DS rich in Ga1NAc(4,6SO(4)) residues participate in the progression or resolution of liver fibrosis. Methods: Wild type (WT) and Ga1NAc4S-6ST KO mice were treated with CCl4 for 5 weeks. After discontinuation of CC14 administration, histochemical and biochemical changes and expression of genes related to matrix components were compared between WT and GalNAc4S-6ST KO mice. Results and conclusion: On 2 days after cessation of CCl4 administration, higher fibrosis was observed in KO mice than in WT mice by Sirius Red staining. Serum alanine aminotransferase activity was higher in KO mice than in WT mice. Hydroxyproline contents and Sirius Red staining showed that repair of liver fibrosis in the recovery stages appeared to be delayed in KO mice. Expression of mRNA of matrix metalloproteinase (MMP)-2, MMP-13 and versican peaked at 2 days after cessation of CCl4 administration and was higher in KO mice than in WT mice. Expression of MMP-9 in the recovery stage was lower in KO mice than in WT mice. Our findings demonstrate that defect in GaINAc4S-65T, which resulted in disappearance of CS/DS containing GalNAc(4,6504), appear to contribute to progression of liver fibrosis, delayed recovery from fibrosis, and various changes in the expression of proteoglycans and MMPs in carbon tetrachloride treated mice.