γ‐Secretase inhibitors suppress IL‐20‐mediated osteoclastogenesis via Notch signalling and are affected by Notch2 in vitro
γ‐Secretase inhibitors suppress IL‐20‐mediated osteoclastogenesis via Notch signalling and are affected by Notch2 in vitro
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DOI：
10.1111/sji.13169
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发表时间：
2022-04
影响因子：
3.7
通讯作者：
Benyi Yang;Chaoran Fu;Yilin Wu;Yuanbo Liu;Zhen Zhang;Xin Chen;Dongle Wu;Ziqi Gan;Zhengyuan Chen;Yang Cao
中科院分区：
文献类型：
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作者：
Benyi Yang;Chaoran Fu;Yilin Wu;Yuanbo Liu;Zhen Zhang;Xin Chen;Dongle Wu;Ziqi Gan;Zhengyuan Chen;Yang Cao
类风湿性关节炎（RA）是一种累及小关节的慢性免疫性疾病，常引起不可逆的损害。近年来，在滑液中观察到白细胞介素20（IL-20）升高，而在滑膜细胞中观察到IL-20受体过表达。IL-20是一种多效性细胞因子，参与各种免疫疾病。进一步了解IL-20与RA之间的关系有助于确定RA的潜在临床治疗方法。这项研究表明，IL-20可以以剂量依赖性方式调节破骨细胞的分化和功能，同时影响Notch信号的表达。定量逆转录聚合酶链反应和蛋白质印迹法表明，γ分泌酶抑制剂可以逆转IL-20的作用。通过免疫荧光和转染小干扰RNA沉默Notch 2基因，研究Notch 2对IL-20诱导的破骨细胞生成的影响，结果显示Notch 2明显影响关键蛋白NFATc 1和下游破骨细胞蛋白的表达水平。总之，我们发现IL-20通过Notch信号传导以剂量依赖性方式调节破骨细胞生成，主要是通过Notch 2活性。这项研究可能有助于为RA治疗寻找新的靶点。
Rheumatoid arthritis (RA) is a chronic immune disease involving the small joints, which often causes irreversible damage. In recent years, elevated interleukin 20 (IL‐20) has been observed in synovial fluid, while IL‐20 receptor overexpression has been observed in synovial cells. IL‐20 is a pleiotropic cytokine that participates in various immune diseases. Further understanding of the relationship between IL‐20 and RA can help to identify a potential clinical treatment for RA. This study demonstrated that IL‐20 can regulate osteoclast differentiation and function in a dose‐dependent manner, while influencing the expression of Notch signalling. Quantitative reverse transcription polymerase chain reaction and western blotting showed that γ‐secretase‐inhibiting drugs can reverse the effects of IL‐20. The effects of Notch2 on IL‐20‐induced osteoclastogenesis were investigated by immunofluorescence and Notch2 gene silencing via transfection of small interfering RNA; the results showed that Notch2 obviously affected the expression levels of the key protein NFATc1 and downstream osteoclastic proteins. In conclusion, we found that IL‐20 regulated the osteoclastogenesis in a dose‐dependent manner via Notch signalling, primarily by means of Notch2 activity. This study may help to find new targets for RA treatment.