Snail Is a Critical Mediator of Invadosome Formation and Joint Degradation in Arthritis
Snail Is a Critical Mediator of Invadosome Formation and Joint Degradation in Arthritis
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DOI：
10.1016/j.ajpath.2015.10.021
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发表时间：
2016-02-01
影响因子：
6
通讯作者：
Dubois, Claire M.
中科院分区：
文献类型：
--
作者：
Lauzier, Annie;Lavoie, Roxane R.;Dubois, Claire M.
侵袭性成纤维细胞样滑膜细胞介导的进行性软骨破坏是类风湿关节炎（RA）发病机制的中心特征。蜗牛转录因子家族的成员是细胞迁移和侵袭所必需的，但它们在关节破坏中的作用尚不清楚。在此，我们证明了蜗牛对于胶原诱导关节炎（CIA）大鼠和RA患者的滑膜细胞形成细胞外基质降解侵入体结构至关重要。在机制上，蜗牛通过抑制PTEN诱导滑膜细胞细胞外基质降解，导致血小板来源的生长因子受体磷酸化增加，激活磷脂酰肌醇3-激酶/AKT通路。值得注意的是，Snail在CIA大鼠和RA患者的滑膜细胞和组织中过表达，而在CIA关节中敲低Snail可防止软骨侵袭和关节损伤。此外，蜗牛表达与转谷氨酰胺酶2/转化生长因子- β激活的上皮-间质转化基因特征相关。转化生长因子- β和转谷氨酰胺酶2刺激大鼠和人滑膜细胞中蜗牛依赖的侵入体形成。我们的研究结果确定了蜗牛- pten血小板衍生的生长因子受体/磷脂酰肌醇3激酶轴是滑膜细胞前破坏性侵入体形成表型的一种新的调节剂。针对类风湿性关节炎的新疗法以炎症为目标，在预防关节损伤方面仅部分有效。阻断螺蛳和/或其相关基因表达程序可能提供一种额外的工具，以提高治疗效果，防止关节破坏。
Progressive cartilage destruction, mediated by invasive fibroblast-like synoviocytes, is a central feature in the pathogenesis of rheumatoid arthritis (RA). Members of the Snail family of transcription factors are required for cell migration and invasion, but their role in joint destruction remains unknown. Herein, we demonstrate that Snail is essential for the formation of extracellular matrix degrading invadosomal structures by synovial cells from collagen-induced arthritis (CIA) rats and RA patients. Mechanistically, Snail induces extracellular matrix degradation in synovial cells by repressing PTEN, resulting in increased phosphorylation of platelet-derived growth factor receptor and activation of the phosphatidylinositol 3-kinase/AKT pathway. Of significance, Snail is overexpressed in synovial cells and tissues of CIA rats and RA patients, whereas knockdown of Snail in CIA joints prevents cartilage invasion and joint damage. Furthermore, Snail expression is associated with an epithelial-mesenchymal transition gene signature characteristic of transglutaminase 2/transforming growth factor-beta activation. Transforming growth factor-beta and transglutaminase 2 stimulate Snail-dependent invadosome formation in rat and human synoviocytes. Our results identify the Snail-PTEN platelet-derived growth factor receptor/phosphatidylinositol 3-kinase axis as a novel regulator of the prodestructive invadosome-forming phenotype of synovial cells. New therapies for RA target inflammation, and are only partly effective in preventing joint damage. Blocking Snail and/or its associated gene expression program may provide an additional tool to improve the efficacy of treatments to prevent joint destruction.