Objectives To investigate the role of tyrosine kinase Fyn in the development of osteoarthritis (OA) and the underlying mechanisms, and to define whether targeting Fyn could prevent OA in mice. Methods Cartilage samples from normal and aged mice were analysed with proteome-wide screening. Fyn expression was examined with immunofluorescence in human and age-dependent or experimental mouse OA cartilage samples. Experimental OA in Fyn-knockout mice was induced by destabilisation of the medial meniscus. Primary cultured mouse chondrocytes were treated with proinflammatory cytokine interleukin-1β. The inhibitor of Src kinase family, AZD0530 (saracatinib), and inhibitor of Fyn, PP1, were used to treat experimental OA in mice. Results Fyn expression was markedly upregulated in human OA cartilage and in cartilage from aged mice and those with post-traumatic OA. Fyn accumulates in articular chondrocytes and interacts directly with and phosphorylates β-catenin at Tyr142, which stabilises β-catenin and promotes its nuclear translocation. The deletion of Fyn effectively delayed the development of post-traumatic and age-dependent OA in mice. Fyn inhibitors AZD0530 and PP1 significantly attenuated OA progression by blocking the β-catenin pathway and reducing the levels of extracellular matrix catabolic enzymes in the articular cartilage. Conclusions Fyn accumulates and activates β-catenin signalling in chondrocytes, accelerating the degradation of the articular cartilage and OA development. Targeting Fyn is a novel and potentially therapeutic approach to the treatment of OA.

中文翻译：

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酪氨酸激酶 Fyn 通过激活 β-catenin 通路促进骨关节炎

目的 研究酪氨酸激酶 Fyn 在骨关节炎 (OA) 发展中的作用及其潜在机制，并确定靶向 Fyn 是否可以预防小鼠骨关节炎。方法使用全蛋白质组筛选分析来自正常和老年小鼠的软骨样本。Fyn 表达在人类和年龄依赖性或实验性小鼠 OA 软骨样本中进行了免疫荧光检测。Fyn 基因敲除小鼠的实验性 OA 是由内侧半月板的不稳定引起的。用促炎细胞因子白细胞介素 1β 处理原代培养的小鼠软骨细胞。Src 激酶家族抑制剂 AZD0530（沙拉卡替尼）和 Fyn 抑制剂 PP1 用于治疗小鼠实验性骨关节炎。结果 Fyn 表达在人 OA 软骨和来自老年小鼠和创伤后 OA 的软骨中显着上调。Fyn 在关节软骨细胞中积累，并在 Tyr142 处直接与 β-catenin 相互作用并使其磷酸化，从而稳定 β-catenin 并促进其核易位。Fyn 的缺失有效地延迟了小鼠创伤后和年龄依赖性 OA 的发展。Fyn 抑制剂 AZD0530 和 PP1 通过阻断 β-连环蛋白途径和降低关节软骨中细胞外基质分解代谢酶的水平，显着减缓了 OA 的进展。结论 Fyn 在软骨细胞中积累并激活 β-catenin 信号，加速关节软骨的降解和 OA 的发展。靶向 Fyn 是一种治疗 OA 的新型潜在治疗方法。