Tyrosine kinase Fyn promotes osteoarthritis by activating the -catenin pathway
Tyrosine kinase Fyn promotes osteoarthritis by activating the -catenin pathway
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酪氨酸激酶 Fyn 通过激活 β-连环蛋白途径促进骨关节炎
DOI：
10.1136/annrheumdis-2017-212658
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发表时间：
2018-06-01
影响因子：
27.4
通讯作者：
Bai, Xiaochun
中科院分区：
文献类型：
--
作者：
Li, Kai;Zhang, Yue;Bai, Xiaochun
目的 探讨酪氨酸激酶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是否能预防小鼠的OA。
方法 对正常小鼠和老年小鼠的软骨样本进行全蛋白质组筛选分析。采用免疫荧光法检测人以及年龄相关性或实验性小鼠OA软骨样本中Fyn的表达。通过内侧半月板失稳诱导Fyn基因敲除小鼠产生实验性OA。用促炎细胞因子白细胞介素 - 1处理原代培养的小鼠软骨细胞。采用Src激酶家族抑制剂AZD0530（萨拉卡替尼）和Fyn抑制剂PP1治疗小鼠实验性OA。
结果 Fyn在人OA软骨以及老年小鼠和创伤后OA小鼠的软骨中表达显著上调。Fyn在关节软骨细胞中积聚，并直接与β - 连环蛋白相互作用，使其在Tyr142位点磷酸化，从而稳定β - 连环蛋白并促进其核转位。Fyn的缺失有效延缓了小鼠创伤后和年龄相关性OA的发展。Fyn抑制剂AZD0530和PP1通过阻断β - 连环蛋白通路并降低关节软骨中细胞外基质分解代谢酶的水平，显著减轻了OA的进展。
结论 Fyn在软骨细胞中积聚并激活β - 连环蛋白信号传导，加速关节软骨的降解和OA的发展。靶向Fyn是一种治疗OA的新的潜在治疗方法。
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.