Inhibition of glycogen synthase kinase 3β induces dermal fibrosis by activation of the canonical Wnt pathway
Inhibition of glycogen synthase kinase 3β induces dermal fibrosis by activation of the canonical Wnt pathway
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DOI：
10.1136/ard.2010.147140
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发表时间：
2011-12-01
影响因子：
27.4
通讯作者：
Distler, Joerg H. W.
中科院分区：
文献类型：
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作者：
Bergmann, Christina;Akhmetshina, Alfiya;Distler, Joerg H. W.
目的糖原合成酶激酶3 β（Glycogen synthase kinase 3 beta，GSK-3）通过调节β-catenin的磷酸化和降解，阻止经典Wnt通路的异常激活。本研究旨在明确GSK-3在成纤维细胞活化和系统性硬化症（SSc）实验模型中的作用。通过测定核β-连环蛋白的水平和通过测量Wnt靶基因Axin 2的mRNA水平来分析经典Wnt信号传导的激活。GSK-3对胶原蛋白释放的影响在人真皮成纤维细胞和在博莱霉素诱导的皮肤纤维化的小鼠模型中在紧皮肤-1（tsk-1）mice.Results靶向GSK-3在体外和体内有效地激活成纤维细胞中的经典Wnt通路。GSK-3的失活以β-连环蛋白依赖性方式剂量依赖性地刺激胶原蛋白从培养的成纤维细胞中释放，并进一步导致小鼠中胶原蛋白的进行性积累和真皮增厚。结论抑制GSK-3可激活成纤维细胞经典的Wnt通路，刺激成纤维细胞胶原释放，加重实验性纤维化，足以诱导纤维化。因此，GSK-3是成纤维细胞中经典Wnt信号传导的关键调节剂，GSK-3的抑制导致成纤维细胞活化和胶原蛋白释放增加。
Objective Glycogen synthase kinase 3 beta (GSK-3) regulates the phosphorylation and subsequent degradation of beta-catenin, thereby preventing aberrant activation of the canonical Wnt pathway. A study was undertaken to define the role of GSK-3 in fibroblast activation and in experimental models of systemic sclerosis (SSc).Methods siRNA and specific inhibitors were used to inhibit GSK-3 in cultured fibroblasts and in mice. Activation of the canonical Wnt signalling was analysed by determining the levels of nuclear beta-catenin and by measuring the mRNA levels of the Wnt target gene Axin2. The effects of GSK-3 on the release of collagen were evaluated in human dermal fibroblasts and in the mouse model of bleomycin-induced skin fibrosis in tight-skin-1 (tsk-1) mice.Results Targeting GSK-3 potently activated the canonical Wnt pathway in fibroblasts in vitro and in vivo. Inactivation of GSK-3 dose-dependently stimulated the release of collagen from cultured fibroblasts in a beta-catenin-dependent manner and further resulted in progressive accumulation of collagen and dermal thickening in mice. Inhibition of GSK-3 aggravated experimental fibrosis in bleomycin-challenged mice and in tsk-1 mice.Conclusion Inhibition of GSK-3 activates the canonical Wnt pathway in fibroblasts, stimulates the release of collagen from fibroblasts, exacerbates experimental fibrosis and is sufficient to induce fibrosis. GSK-3 is therefore a key regulator of the canonical Wnt signalling in fibroblasts and inhibition of GSK-3 results in fibroblast activation and increased release of collagen.