Sulfatase-2 Regulates Liver Fibrosis through the TGF-β Signaling Pathway

Abstract

Transforming growth factor-β (TGF-β) activates hepatic stellate cells (HSCs), which drive liver fibrosis via the production and deposition of extracellular matrix (ECM). We aimed to elucidate the mechanistic role of sulfatase-2 (SULF2) in liver fibrosis. To this end, we induced liver fibrosis in wild-type (WT) and SULF2 knockout (Sulf2-KO) mice (6–8 weeks-old) via bile duct ligation (BDL), intraperitoneal injection of carbon tetrachloride (CCl4) or thioacetamide (TAA). The levels of fibrosis in the liver sections were assessed via Sirius red and Masson’s trichrome staining, immunohistochemistry and immunoblotting for α-smooth muscle actin (α-SMA) and hydroxyproline. To evaluate the interaction between TGF-β and SULF2, we transfected human HSCs with scrambled control shRNA and shRNA constructs targeting SULF2 and measured α-SMA expression following treatment with TGF-β1 ligand. We show here that knockout of SULF2 significantly decreases collagen content, as well as bands of bridging fibrosis, as demonstrated by Sirius red, Masson’s trichrome and α-SMA staining after BDL, CCl4 and TAA injection in Sulf2-KO versus WT mice. In all three models of liver fibrosis, we observed significantly lower levels of hydroxyproline in the Sulf2-KO mice compared to the WT mice. HSCs with reduced levels of SULF2 failed to significantly express α-SMA and collagen type I following treatment with TGF-β1. Furthermore, SULF2 co-localizes with TGFBR3 and the in vitro knockdown of SULF2 in HSCs decreases the release of TGF-β1 from TGFBR3. Together, these data suggest that SULF2 regulates liver fibrosis via the TGF-β signaling pathway. Pharmacologic inhibition of SULF2 may represent a novel therapeutic approach to improve liver fibrosis.

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“…Histological examination, fibrosis grading, and hydroxyproline content in the hepatic tissue were performed to evaluate the ability of CCl 4 to induce hepatic fibrosis. Total collagen, determined by hydroxyproline quantification as hydroxyproline, is an indicator of the collagen deposition [ 50 ]. CCl 4 -administered animals exhibited a significantly higher hydroxyproline content, which is in harmony with previous studies [ 51 ].…”

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“…SULF2, a 6-O sulfatase of the extracellular matrix (ECM), desulfates heparan sulfate proteoglycans (HSPGs), releasing growth factors and cytokines from storage sites and activating downstream signaling pathways, including FGF, VEGF, PDGF, IL-6, TGFβ, and WNT [ 46 ]. SULF2 influences fibrotic liver disease by interacting with the TGF-β1/Smad pathway, and it appears that Transforming Growth Factor Beta Receptor 3 (TGFBR3) plays a significant role in mediating the activation of the TGF-β1 signaling pathway by SULF2 [ 47 ]. While variations in the SULF2 gene have been documented and linked to the pathogenesis of several diseases, there is currently no reported association with COPD or other lung diseases.…”

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“…TGF-β is the most fibrogenic cytokine in the liver [ 63 , 64 ] and contains three subtypes: TGF-β1, TGF-β2, and TGF-β3 [ 65 ]. Under the stimulation of TGF-β, HSCs start to differentiate from a quiescent state into proliferative and fibrotic myofibroblasts that express and secrete α-SMA and collagen types I (CoI-l), CoI-III, and CoI-IV, leading to liver fibrosis [ 7 ].…”