Low dose of indomethacin and Hedgehog signaling inhibitor administration synergistically attenuates cartilage damage in osteoarthritis by controlling chondrocytes pyroptosis
Low dose of indomethacin and Hedgehog signaling inhibitor administration synergistically attenuates cartilage damage in osteoarthritis by controlling chondrocytes pyroptosis
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DOI：
10.1016/j.gene.2019.143959
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发表时间：
2019-09-05
期刊：
影响因子：
3.5
通讯作者：
Liu, Gang
中科院分区：
文献类型：
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作者：
Liu, Qingbai;Wu, Zaifeng;Liu, Gang
阻断Hedgehog信号传导可以预防骨关节炎（OA）综合征。然而，相关炎症状况的改善有限。本研究旨在观察Hedgehog信号通路抑制剂GANT-61与临床常用抗炎药吲哚美辛联合应用对实验性OA小鼠软骨损伤和炎症的影响。我们发现GANT-61和吲哚美辛协同减轻OA小鼠的软骨损伤和炎性细胞因子TNF-α、IL-2和IL-6的血清水平。此外，在体外治疗GANT-61和吲哚美辛协同降低TNF-α，IL-2和IL-6的mRNA表达的脂多糖（LPS）刺激的C28/I2软骨细胞。GANT-61和吲哚美辛在mRNA和蛋白水平协同抑制细胞凋亡相关基因caspase-1、IL-1 β和IL-18的表达。综上所述，我们的研究表明GANT-61和吲哚美辛通过介导软骨细胞焦亡对骨关节炎具有协同改善作用。
Blockade of Hedgehog signaling can prevent osteoarthritis (OA) syndromes. However, the amelioration of related inflammation condition is limited. The purpose of this study was to observe the effect of combined use of Hedgehog signaling inhibitor GANT-61 and common clinical anti-inflammatory drug indomethacin on cartilage injury and inflammation in experimental OA mice. We found that GANT-61 and indomethacin synergistically attenuate cartilage damage and serum levels of inflammatory cytokines TNF-alpha, IL-2 and IL-6 in OA mice. Moreover, in vitro treatment of GANT-61 and indomethacin synergistically reduced the mRNA expression of TNF-alpha, IL-2 and IL-6 in lipopolysaccharide (LPS)-stimulated C28/I2 chondrocytes. Mechasnistic studies showed that GANT-61 and indomethacin synergistically attenuate the expressions of cell pyroptosis-related genes caspase-1, IL-1 beta and IL-18 at mRNA and protein level. To conclude, our study showed that GANT-61 and indomethacin had a synergistically ameliorating effect on osteoarthritis by mediating chondrocytes pyroptosis.