Translational Liver Research, Department of Medical Cell BioPhysics, Technical Medical Centre, Faculty of Science and Technology, University of Twente, 7522 NB Enschede, The Netherlands.
Cells. 2020 May 13;9(5):1212. doi: 10.3390/cells9051212.
Chronic liver diseases, characterized by an excessive accumulation of extracellular matrix (ECM) resulting in scar tissue formation, are a growing health problem causing increasing morbidity and mortality worldwide. Currently, therapeutic options for tissue fibrosis are severely limited, and organ transplantation is the only treatment for the end-stage liver diseases. During liver damage, injured hepatocytes release proinflammatory factors resulting in the recruitment and activation of immune cells that activate quiescent hepatic stellate cells (HSCs). Upon activation, HSCs transdifferentiate into highly proliferative, migratory, contractile and ECM-producing myofibroblasts. The disrupted balance between ECM deposition and degradation leads to the formation of scar tissue referred to as fibrosis. This balance can be restored either by reducing ECM deposition (by inhibition of HSCs activation and proliferation) or enhancing ECM degradation (by increased expression of matrix metalloproteinases (MMPs)). MMPs play an important role in ECM remodeling and represent an interesting target for therapeutic drug discovery. In this review, we present the current knowledge about ECM remodeling and role of the different MMPs in liver diseases. MMP expression patterns in different stages of liver diseases have also been reviewed to determine their role as biomarkers. Finally, we highlight MMPs as promising therapeutic targets for the resolution of liver diseases.
慢性肝脏疾病的特征是细胞外基质（ECM）的过度积累，导致疤痕组织形成，这是一个日益严重的健康问题，在全球范围内导致发病率和死亡率不断上升。目前，针对组织纤维化的治疗选择非常有限，器官移植是治疗终末期肝病的唯一方法。在肝损伤过程中，受损的肝细胞释放促炎因子，导致免疫细胞的募集和激活，从而激活静止的肝星状细胞（HSCs）。HSCs 激活后，向高度增殖、迁移、收缩和 ECM 产生的肌成纤维细胞分化。ECM 沉积和降解之间的平衡被打破，导致形成称为纤维化的疤痕组织。这种平衡可以通过减少 ECM 沉积（通过抑制 HSCs 的激活和增殖）或增强 ECM 降解（通过增加基质金属蛋白酶（MMPs）的表达）来恢复。MMPs 在 ECM 重塑中发挥重要作用，是治疗药物发现的一个有趣靶点。在这篇综述中，我们介绍了 ECM 重塑的最新知识，以及不同 MMPs 在肝脏疾病中的作用。还回顾了不同阶段肝脏疾病中 MMP 的表达模式，以确定它们作为生物标志物的作用。最后，我们强调了 MMPs 作为解决肝脏疾病的有前途的治疗靶点。
