Gremlin1 Accelerates Hepatic Stellate Cell Activation Through Upregulation of TGF-Beta Expression

Abstract

Gremlin1, the antagonist of bone morphogenetic protein-7 and one of the target genes of transforming growth factor (TGF)-β signal pathway, plays an important role in embryonic development and its expression decreases along with aging. To explore the expression of gremlin1 in liver fibrosis and the causal link between gremlin1 and hepatic stellate cell (HSC) activation, we detected the expression of gremlin1 in mice with hepatic fibrosis induced by porcine serum using real time quantitative PCR (RT-qPCR) and immunohistochemical staining. The hepatic fibrosis mice were evaluated by the external feature of the liver, histology, hepatic function, collagen deposition, and the expression of fibrosis-related genes (genes COLIα2 and COLIVα2) in the liver. In the HSC-T6, western blotting was used to analyze the expression of α-smooth muscle actin (α-SMA), COL1α, and TGF-β1 in conditions of overexpression of gremlin1 or gremlin1 being knocked down by specific siRNA, respectively. The results showed that the mRNA expression of the gremlin1 gene was significantly increased consistent with increased expression of COLIα2 and COLIVα2 in the liver tissue of the hepatic fibrosis mice. Increased expression of gremlin1 coincided with the same area of the collagen deposition. Furthermore, the results also showed that the expression of α-SMA, COLIα1, and TGF-β1 was consistent with the expression of gremlin1 not only in the HSC-T6 overexpressing gremlin1 but also in the HSC-T6 that gremlin1 is knocked down by specific siRNA. The findings suggest that gremlin1 might play an important role in the progression of hepatic fibrosis and that it modulates HSC activation.

Overexpression of mircoRNA-137 inhibits cervical cancer cell invasion, migration and epithelial–mesenchymal transition by suppressing the TGF-β/smad pathway via binding to GREM1

“…However, there was very little literature demonstrating the mechanism of GREM1 in CC. Moreover, some studies have revealed that GREM1 is most likely to participate in the regulation of the TGF-β pathway, which has been verified as an essential pathway involved in the progression of CC [18–20]. The differential expression analysis of GSE63514 identified a notable upregulation of GREM1 level in CC tissues.…”

TGF-β in Hepatic Stellate Cell Activation and Liver Fibrogenesis—Updated 2019

“…In addition, gremlin1, a TGF-β target gene, acts as antagonist of BMP7. It was upregulated in the porcine serum-induced hepatic fibrosis model [92]. Taking into consideration the antagonistic functions of BMP7 and TGF-β in liver fibrosis, gremlin1 could act as a bridge connecting these two signaling pathways [10].…”

BMP Signalling at the Crossroad of Liver Fibrosis and Regeneration

“…Interestingly, upregulation of gremlin was observed in animal models of liver fibrosis and in cirrhotic patients [ 138 , 139 , 140 ] and it is expressed in fully activated HSC, which suggest its involvement in the process of activation into myofibroblasts. Indeed, Zhang et al found a direct correlation between gremlin expression in HSCs and expression of fibrosis markers, αSMA, Col1a, TGF-β, proposing an important role for gremlin in HSC activation via upregulation of TGF-β and likely inhibiting BMP7 protective signals [ 140 ]. At the same time, BMP7 positively regulates gremlin expression while suppresses TGF-β expression [ 139 ].…”

“…On this respect, it is also necessary to keep in mind that endoglin could modulate the actions of other BMP ligands, such as BMP2 and BMP7 [ 146 , 147 ]. We should not ignore either that activated HSCs show an altered expression pattern of BMPs modulators, specifically, high levels of gremlin and endoglin and lower levels of Bambi, as compared to normal HSC [ 133 , 134 , 140 , 171 ]. How the altered expression of these modulators affects BMPs signalling and final cell response is not known but we could hypothesize on an inhibition of BMP antifibrotic effects and promotion of profibrotic signals.…”