Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Germany.
Ann Rheum Dis. 2011 Dec;70(12):2191-8. doi: 10.1136/ard.2010.147140. Epub 2011 Aug 25.
Glycogen synthase kinase 3β (GSK-3) regulates the phosphorylation and subsequent degradation of β-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).
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 β-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.
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 β-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.
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.
糖原合成酶激酶 3β（GSK-3β）调节β-连环蛋白的磷酸化和随后的降解，从而防止经典 Wnt 途径的异常激活。本研究旨在确定 GSK-3 在成纤维细胞激活和系统性硬化症（SSc）实验模型中的作用。
使用 siRNA 和特异性抑制剂抑制培养的成纤维细胞和小鼠中的 GSK-3。通过测定核β-连环蛋白水平和测量 Wnt 靶基因 Axin2 的 mRNA 水平来分析经典 Wnt 信号的激活。通过在人真皮成纤维细胞和硬皮病-1（tsk-1）小鼠的博来霉素诱导皮肤纤维化模型中评估 GSK-3 对胶原释放的影响。
靶向 GSK-3 可在体外和体内强力激活成纤维细胞中的经典 Wnt 途径。GSK-3 的失活以β-连环蛋白依赖性方式剂量依赖性地刺激培养的成纤维细胞中胶原的释放，并进一步导致胶原的进行性积累和小鼠皮肤增厚。在博来霉素挑战的小鼠和 tsk-1 小鼠中，GSK-3 的抑制加重了实验性纤维化。
GSK-3 抑制激活成纤维细胞中的经典 Wnt 途径，刺激成纤维细胞释放胶原，加重实验性纤维化，并足以诱导纤维化。因此，GSK-3 是成纤维细胞中经典 Wnt 信号的关键调节剂，GSK-3 的抑制导致成纤维细胞激活和胶原释放增加。
