Hepatic stellate cells (HSCs) are known to play a key role in the progression of liver fibrosis by producing excessive extracellular matrix (ECM). Matrix metalloproteinases (MMPs) belong to a family of endopeptidases, which have a well-established role in the degradation of ECM. Our study suggests that, besides the degradation of the extracellular matrix, matrix metalloproteinase-8 (MMP-8) has a non-canonical role in activating the quiescent HSCs to myofibroblasts by regulating the expression of Col1A1 and αSMA. We have identified that MMP-8 secreted from macrophages as a response to LPS stimulation activates HSCs via ERK1/2-dependent pathway. In addition to this, we determined that MMP-8 may regulate the homodimerization of c-Jun in LX-2 cells, during the trans-differentiation process from quiescent HSC to activate myofibroblasts. Macrophage-released MMP-8 plays a master role in activating the dormant HSCs to activate myofibroblasts through the Erk-mediated pathway and Jun cellular translocation leading to liver fibrosis. Significance MMP-8 can be used as a therapeutic target against liver fibrosis.

中文翻译：

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基质金属蛋白酶8（MMP-8）通过ERK介导的途径调节肝星状细胞（HSC）的活化。

众所周知，肝星状细胞（HSC）通过产生过量的细胞外基质（ECM）在肝纤维化进程中起关键作用。基质金属蛋白酶（MMP）属于内肽酶家族，在ECM降解中具有公认的作用。我们的研究表明，除细胞外基质降解外，基质金属蛋白酶8（MMP-8）通过调节Col1A1和αSMA的表达在激活静态HSCs向成纤维细胞中具有非典型作用。我们已经发现巨噬细胞分泌的MMP-8作为对LPS刺激的应答，通过ERK1 / 2依赖性途径激活HSC。除此之外，我们还确定了MMP-8可能在静态HSC激活肌成纤维细胞的转分化过程中，调节LX-2细胞中c-Jun的均二聚化。巨噬细胞释放的MMP-8在激活休眠的HSC中起主要作用，以通过Erk介导的途径和Jun细胞移位导致肌纤维母细胞活化，从而导致肝纤维化。意义MMP-8可用作抗肝纤维化的治疗靶标。