Ablation of the decorin gene enhances experimental hepatic fibrosis and impairs hepatic healing in mice.
Ablation of the decorin gene enhances experimental hepatic fibrosis and impairs hepatic healing in mice.
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DOI：
10.1038/labinvest.2010.172
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发表时间：
2011-03
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结缔组织堆积是慢性肝病的典型特征。核心蛋白聚糖是一种富含亮氨酸的蛋白多糖，在发育过程中调节胶原纤维的形成，并通过直接阻断转化生长因子-β-1(转化生长因子-β-1)的生物活性，发挥抗纤维化的作用。然而，之前还没有关于核心蛋白聚糖在肝脏中的作用的体内研究。在这项研究中，我们利用核心蛋白聚糖缺失(Dcn−/−)小鼠来确定核心蛋白聚糖在实验性肝纤维化和修复中的作用。与野生型小鼠相比，Dcn−/−动物不仅实验诱导的肝纤维化程度更严重，而且愈合过程也明显延迟。−/−肝组织中I型、III型和IV型胶原的表达水平仅在前两个月高于野生型，但在诱导肝纤维化的4个月后无明显差异，提示这些蛋白的升高反映了其降解的特定损害。明胶酶检测证实了这一假说，我们发现DCN−/−肝组织中MMP2和MMP9活性降低，TIMP1和PAI1mRNA表达增加。相反，在恢复阶段结束时，dcn−/−小鼠肝脏中结缔组织过度沉积的原因被发现是产量的增加而不是降解的减弱。转化生长因子β1诱导的早期反应基因在核心蛋白缺失的肝脏中的高表达表明转化生长因子β1的生物活性增强，该活性也可上调TIMP-1和PAI-1。此外，核心蛋白聚糖缺乏影响了转化生长因子Smad1信号通路的两个主轴，即β1/2和Smad3在Dcn−/−样本中被激活，而磷酸化Smad2在不同基因类型的小鼠之间没有显著差异。总而言之，我们的结果表明，核心蛋白聚糖的缺乏有利于肝纤维化的发展，并至少部分地通过影响转化生长因子β1的生物活性来延缓随后的愈合过程。
Accumulation of connective tissue is a typical feature of chronic liver diseases. Decorin, a small leucine-rich proteoglycan, regulates collagen fibrillogenesis during development, and by directly blocking the bioactivity of transforming growth factor-β1 (TGFβ1), it exerts a protective effect against fibrosis. However no in vivo investigations on the role of decorin in liver have been performed before. In this study we utilized decorin-null (Dcn−/−) mice to establish the role of decorin in experimental liver fibrosis and repair. Not only the extent of experimentally-induced liver fibrosis was more severe in Dcn−/− animals, but also the healing process was significantly delayed vis-à-vis wild-type mice. Collagen I, III, and IV mRNA levels in Dcn−/−livers were higher than those of wild-type livers only in the first two months, but no difference was observed after four months of fibrosis induction, suggesting that the elevation of these proteins reflects a specific impairment of their degradation. Gelatinase assays confirmed this hypothesis as we found decreased MMP-2 and MMP-9 activity and higher expression of TIMP-1 and PAI-1 mRNA in Dcn−/− livers. In contrast, at the end of the recovery phase increased production rather than impaired degradation was found to be responsible for the excessive connective tissue deposition in livers of Dcn−/− mice. Higher expression of TGFβ1-inducible early responsive gene in decorin-null livers indicated enhanced bioactivity of TGFβ1 known to upregulate TIMP-1 and PAI-1, as well. Morever, two main axes of TGFβ1-evoked signaling pathways were affected by decorin deficiency, namely the Erk1/2 and Smad3 were activated in Dcn−/− samples, while no significant difference in phospho-Smad2 was observed between mice with different genotypes. Collectively, our results indicate that the lack of decorin favors the development of hepatic fibrosis and attenuates its subsequent healing process at least in part by affecting the bioactivity of TGFβ1.