Chronic inflammation, mainly derived from fibroblast-like synoviocytes (FLSs), plays a central role in the pathomechanism of osteoarthritis (OA). Recently, epithelial-mesenchymal transition (EMT) signaling was found to be activated in OA-derived FLSs with a pro-inflammatory phenotype. However, the role of EMT signaling in regulating FLS function and OA-related inflammation remains unknown. The synovium of OA patients were evaluated for EMT and inflammation markers. The FLSs with activated EMT signaling were co-cultured with chondrocytes (chond). Gene expression of OA synovial samples were analyzed. The role of receptor tyrosine kinase C-kit was investigated in OA-FLSs and an OA rat model. The downstream pathways driven by C-kit were explored in OA-FLSs. EMT marker N-cadherin (N-CDH) was upregulated in 40.0% of the OA samples. These N-CDH+ OA samples showed higher expression of pro-inflammatory factors. In co-culture, FLSs derived from N-CDH+ OA samples induced a typical degenerative phenotype of chonds and stimulated their production of matrix degrading enzymes. C-kit was significantly upregulated and spatially co-localized with N-CDH in N-CDH+ OA samples. In OA-FLSs, C-kit activated intracellular EMT signaling and induced destructive features of OA-FLSs. In OA rat model, C-kit largely promoted synovial inflammation and cartilage destruction, whereas knocking-down C-kit significantly restored the health of OA joints. Using GSK3β S9A mutant, we demonstrated that C-kit drives EMT signaling in OA-FLS by promoting phosphorylation of GSK3β and nuclear retention of the EMT transcription factor Snail. C-kit drives EMT signaling in OA-FLSs and promotes a destructive FLS phenotype, leading to synovial inflammation and cartilage destruction.

中文翻译：

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受体酪氨酸激酶 C-kit 通过细胞内 EMT 信号传导促进骨关节炎中 FLS 的破坏性表型

慢性炎症主要来源于成纤维样滑膜细胞（FLS），在骨关节炎（OA）的病理机制中发挥着核心作用。最近，发现 OA 衍生的具有促炎表型的 FLS 中上皮间质转化 (EMT) 信号被激活。然而，EMT 信号在调节 FLS 功能和 OA 相关炎症中的作用仍不清楚。对 OA 患者滑膜进行 EMT 和炎症标志物评估。将具有激活的 EMT 信号传导的 FLS 与软骨细胞 (chond) 共培养。分析了 OA 滑液样本的基因表达。在 OA-FLS 和 OA 大鼠模型中研究了受体酪氨酸激酶 C-kit 的作用。在 OA-FLS 中探索了 C-kit 驱动的下游途径。EMT 标记物 N-钙粘蛋白 (N-CDH) 在 40.0% 的 OA 样本中表达上调。这些 N-CDH+ OA 样本显示出较高的促炎因子表达。在共培养中，源自 N-CDH+ OA 样品的 FLS 诱导了典型的软骨退化表型，并刺激其产生基质降解酶。在 N-CDH+ OA 样本中，C-kit 显着上调并与 N-CDH 空间共定位。在 OA-FLS 中，C-kit 激活细胞内 EMT 信号传导并诱导 OA-FLS 的破坏性特征。在 OA 大鼠模型中，C-kit 在很大程度上促进了滑膜炎症和软骨破坏，而敲除 C-kit 则显着恢复了 OA 关节的健康。使用 GSK3β S9A 突变体，我们证明 C-kit 通过促进 GSK3β 的磷酸化和 EMT 转录因子 Snail 的核保留来驱动 OA-FLS 中的 EMT 信号传导。C-kit 驱动 OA-FLS 中的 EMT 信号传导并促进破坏性 FLS 表型，导致滑膜炎症和软骨破坏。