Kapoor Mohit, Liu Shangxi, Shi-wen Xu, Huh Kun, McCann Matthew, Denton Christopher P, Woodgett James R, Abraham David J, Leask Andrew
Division of Oral Biology and Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada.
J Clin Invest. 2008 Oct;118(10):3279-90. doi: 10.1172/JCI35381.
Glycogen synthase kinase-3 (GSK-3) is a widely expressed and highly conserved serine/threonine protein kinase encoded by 2 genes, GSK3A and GSK3B. GSK-3 is thought to be involved in tissue repair and fibrogenesis, but its role in these processes is currently unknown. To investigate the function of GSK-3beta in fibroblasts, we generated mice harboring a fibroblast-specific deletion of Gsk3b and evaluated their wound-healing and fibrogenic responses. We have shown that Gsk3b-conditional-KO mice (Gsk3b-CKO mice) exhibited accelerated wound closure, increased fibrogenesis, and excessive scarring compared with control mice. In addition, Gsk3b-CKO mice showed elevated collagen production, decreased cell apoptosis, elevated levels of profibrotic alpha-SMA, and increased myofibroblast formation during wound healing. In cultured Gsk3b-CKO fibroblasts, adhesion, spreading, migration, and contraction were enhanced. Both Gsk3b-CKO mice and fibroblasts showed elevated expression and production of endothelin-1 (ET-1) compared with control mice and cells. Antagonizing ET-1 reversed the phenotype of Gsk3b-CKO fibroblasts and mice. Thus, GSK-3beta appears to control the progression of wound healing and fibrosis by modulating ET-1 levels. These results suggest that targeting the GSK-3beta pathway or ET-1 may be of benefit in controlling tissue repair and fibrogenic responses in vivo.
糖原合酶激酶-3（GSK-3）是一种广泛表达且高度保守的丝氨酸/苏氨酸蛋白激酶，由GSK3A和GSK3B这两个基因编码。GSK-3被认为参与组织修复和纤维化形成，但其在这些过程中的作用目前尚不清楚。为了研究GSK-3β在成纤维细胞中的功能，我们构建了成纤维细胞特异性缺失Gsk3b的小鼠，并评估了它们的伤口愈合和纤维化反应。我们发现，与对照小鼠相比，Gsk3b条件性敲除小鼠（Gsk3b-CKO小鼠）表现出伤口闭合加速、纤维化形成增加和过度瘢痕形成。此外，Gsk3b-CKO小鼠在伤口愈合过程中显示出胶原蛋白生成增加、细胞凋亡减少、促纤维化α-SMA水平升高以及肌成纤维细胞形成增加。在培养的Gsk3b-CKO成纤维细胞中，黏附、铺展、迁移和收缩均增强。与对照小鼠和细胞相比，Gsk3b-CKO小鼠和成纤维细胞均显示内皮素-1（ET-1）的表达和生成增加。拮抗ET-1可逆转Gsk3b-CKO成纤维细胞和小鼠的表型。因此，GSK-3β似乎通过调节ET-1水平来控制伤口愈合和纤维化的进程。这些结果表明，靶向GSK-3β途径或ET-1可能有助于控制体内的组织修复和纤维化反应。
