Jin Feng, Liao Leming, Zhu Yongjun
Department of Orthopedics, Community Health Service Center of Shouxiang, Hangzhou, Zhejiang Province, China.
Department of Orthopedics, First People's Hospital of Fuyang District, Hangzhou, Zhejiang Province, China.
Int J Immunogenet. 2021 Oct;48(5):435-442. doi: 10.1111/iji.12534. Epub 2021 Mar 1.
Osteoarthritis (OA) is one of the most common degenerative joint diseases worldwide. Chondrocytes are activated in OA patients, accompanied by excessive chondrogenic proliferation and production of inflammatory cytokines. MiR-467b is implicated in the regulation of artherosclerosis and pro-inflammatory cytokine secretion. However, the precise role of miR-467b in OA remains unclear. In the present study, we induced inflammation in chondrogenic ATDC5 cells using lipopolysaccharide (LPS). LPS treatment significantly elevated the production of interleukin-6 (IL-6), IL-1β and tumour necrosis factor-α (TNF-α) in ATDC5 cells, accompanied by decreased miR-467 level. Then, we over-expressed miR-467b using its specific mimics in ATDC5 cells, and LPS-induced inflammation was significantly inhibited as evidenced by decreased IL-6, IL-1β and TNF-α levels. MiR-467b agomir also alleviated inflammation in rat knee osteoarthritis (KOA) model. In addition, we validated that signal transducer and activator of transcription 1 (STAT1) was a downstream target of miR-467b. LPS treatment significantly increased the STAT1 expression while miR-467b mimic transfection partially reversed this effect. Moreover, STAT1 knockout reversed the increased contents of IL-6, IL-1β and TNF-α. Furthermore, miR-467b over-expression significantly decreased the production of IL-6, IL-1β and TNF-α induced by LPS treatment, which was partially reversed by further STAT1 over-expression. In summary, our findings demonstrated that miR-467b alleviated LPS-induced inflammation through targeting STAT1, and this miR-467b/STAT1 regulation axis may provide a new therapeutic target for OA clinical management.
骨关节炎（OA）是全球最常见的退行性关节疾病之一。OA患者的软骨细胞被激活，同时伴有软骨生成过度增殖和炎性细胞因子的产生。MiR-467b参与动脉粥样硬化和促炎细胞因子分泌的调节。然而，miR-467b在OA中的具体作用仍不清楚。在本研究中，我们使用脂多糖（LPS）诱导软骨生成的ATDC5细胞发生炎症。LPS处理显著提高了ATDC5细胞中白细胞介素-6（IL-6）、IL-1β和肿瘤坏死因子-α（TNF-α）的产生，同时miR-467水平降低。然后，我们在ATDC5细胞中使用其特异性模拟物过表达miR-467b，IL-6、IL-1β和TNF-α水平降低证明LPS诱导的炎症受到显著抑制。MiR-467b激动剂也减轻了大鼠膝骨关节炎（KOA）模型中的炎症。此外，我们验证了信号转导和转录激活因子1（STAT1）是miR-467b的下游靶点。LPS处理显著增加了STAT1的表达，而miR-467b模拟物转染部分逆转了这种效应。此外，STAT1基因敲除逆转了IL-6、IL-1β和TNF-α含量的增加。此外，miR-467b过表达显著降低了LPS处理诱导的IL-6、IL-1β和TNF-α的产生，进一步过表达STAT1可部分逆转这种降低。总之，我们的研究结果表明，miR-467b通过靶向STAT1减轻LPS诱导的炎症，并且这种miR-467b/STAT1调节轴可能为OA临床治疗提供新的治疗靶点。
