Modification of Cysteine 179 in IKKβ by Ursolic Acid Inhibits Titanium-Wear-Particle-Induced Inflammation, Osteoclastogenesis, and Hydroxylapatite Resorption,Molecular Pharmaceutics

当前位置： X-MOL 学术 › Mol. Pharmaceutics › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Modification of Cysteine 179 in IKKβ by Ursolic Acid Inhibits Titanium-Wear-Particle-Induced Inflammation, Osteoclastogenesis, and Hydroxylapatite Resorption
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2018-09-28 00:00:00 , DOI: 10.1021/acs.molpharmaceut.8b00747
Mingzheng Peng ₁ , Lei Qiang ₂ , Yan Xu ₂ , Cuidi Li ₃ , Tao Li ₁ , Jinwu Wang ₁

Affiliation

Aseptic loosening of artificial joints mainly accounts for the failure of arthroplasty. We previously reported that ursolic acid (UA) inhibited osteolysis caused by titanium (Ti) wear particles via suppression of NF-kB signaling. In the present study, that the suppressive effect of UA on Ti-particle-induced inflammation and osteoclastogenesis targets on IKKβ cys-179 was demonstrated. A retrovirus packaged IKKβC179A plasmid with a Cys-179 mutation replaced by Ala was constructed. qRT-PCR, immunoblot, and immunofluorescence were used to evaluate the gene expressions. Secreted inflammatory cytokines were detected by ELISA. Formation and function of osteoclastogenesis were evaluated by TRAP stain and hydroxylapatite resorption assays. As a result, a mutation of IKKβC179A rescued the therapeutic effect of UA on Ti-particle-induced inflammation, including morphological transforms, upregulation of iNOS and COX-2, increased secretions of TNF-α, IL-1β, and IL-6, and decreased secretion of IL-10. Meanwhile, inhibition of osteoclastogenesis and hydroxylapatite resorptions were restored by transfection of IKKβC179A. Phosphorylations of p65 and the IKKα/β complex and translocation of p65 into the nucleus were suppressed by UA but rescued by a mutation of IKKβC179A. Conclusively, UA inhibits Ti-wear-particle-induced inflammation, osteoclastogenesis, and hydroxylapatite resorption via modifying cysteine 179 of IKKβ.

中文翻译：

熊果酸修饰 IKKβ 中的半胱氨酸 179 可抑制钛磨损颗粒引起的炎症、破骨细胞生成和羟基磷灰石吸收

人工关节的无菌性松动是造成人工关节置换术失败的主要原因。我们之前报道过熊果酸 (UA) 通过抑制 NF-kB 信号传导来抑制钛 (Ti) 磨损颗粒引起的骨溶解。在本研究中，证明了UA对钛颗粒诱导的炎症和破骨细胞生成靶点IKKβ cys-179的抑制作用。构建了逆转录病毒包装的IKKβC179A质粒，其中Cys-179突变被Ala取代。 qRT-PCR、免疫印迹和免疫荧光用于评估基因表达。通过ELISA检测分泌的炎症细胞因子。通过TRAP染色和羟基磷灰石吸收测定评估破骨细胞生成的形成和功能。结果，IKKβC179A 的突变挽救了 UA 对钛颗粒诱导的炎症的治疗作用，包括形态学转变、iNOS 和 COX-2 上调、TNF-α、IL-1β 和 IL-6 分泌增加，并减少IL-10的分泌。同时，转染 IKKβC179A 可以恢复对破骨细胞生成和羟基磷灰石吸收的抑制。 p65 和 IKKα/β 复合物的磷酸化以及 p65 易位到细胞核中均被 UA 抑制，但通过 IKKβC179A 的突变得以挽救。总之，UA 通过修饰 IKKβ 的半胱氨酸 179 来抑制钛磨损颗粒诱导的炎症、破骨细胞生成和羟基磷灰石吸收。

更新日期：2018-09-28

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南11