Peri-implant osteolysis (PIO) and the subsequent aseptic loosening are the main reasons for artificial joint implant failure. Existing methods for treating aseptic loosening are far from satisfactory, necessitating advanced drug exploration. This study is aimed at investigating the effect and underlying mechanism of tetrandrine (Tet) on inflammatory osteolysis. We established a Ti particle-induced inflammatory osteolysis mouse model and administered Tet or an equal volume of phosphate-buffered saline (PBS). Two weeks later, specimens were collected. Histological staining showed that Tet administration inhibited Ti-stimulated osteolysis. Tartrate-resistant acid phosphate (TRAP) staining and transmission electron microscopy (TEM) demonstrated that osteoclast formation was remarkably inhibited in the groups treated with Tet in a dose-dependent manner. In addition, relevant inflammatory cytokines (tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6) were also significantly reduced in the calvaria of the Tet-treated groups. Exposure of receptor activator for nuclear factor-κB ligand- (RANKL-) induced bone marrow-derived macrophages (BMMs) and RAW264.7 cells to Tet significantly reduced osteoclast formation, F-actin ring formation, bone resorption, and the expression of relevant genes (matrix metallopeptidase 9 (MMP-9), TRAP, and nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1)) during osteoclastogenesis in vitro. Mechanistic studies using Western blotting demonstrated that Tet inhibited the nuclear factor (NF)-κB signaling pathway by decreasing the phosphorylation of inhibitor of NF-κB α (IκBα) and p65, which play important roles in osteoclast formation. Collectively, our data indicate that Tet suppressed Ti-induced inflammatory osteolysis and osteoclast formation in mice, suggesting that Tet has the potential to be developed to treat and prevent wear particle-induced inflammatory osteolysis.

中文翻译：

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粉防己碱通过核因子-κB 通路抑制钛颗粒诱导的炎症性骨溶解

种植体周围骨质溶解 (PIO) 和随后的无菌性松动是人工关节种植体失败的主要原因。现有的治疗无菌性松动的方法远不能令人满意，需要进一步的药物探索。本研究旨在研究粉防己碱 (Tet) 对炎症性骨溶解的影响和潜在机制。我们建立了 Ti 颗粒诱导的炎症性骨溶解小鼠模型，并给予 Tet 或等体积的磷酸盐缓冲盐水 (PBS)。两周后，标本被收集。组织学染色显示 Tet 给药抑制了 Ti 刺激的骨溶解。抗酒石酸酸性磷酸盐 (TRAP) 染色和透射电子显微镜 (TEM) 表明，在用 Tet 处理的组中，破骨细胞的形成以剂量依赖性方式受到显着抑制。α、白细胞介素 (IL)-1 β和 IL-6) 在 Tet 治疗组的颅骨中也显着降低。受体激活剂的曝光核因子κ乙配体（RANKL-）诱导的骨髓来源的巨噬细胞（两种BMM）和RAW264.7细胞的Tet显著减少破骨细胞形成，F-肌动蛋白环的形成，骨吸收，以及表达体外破骨细胞生成过程中的相关基因（基质金属肽酶 9 ( MMP-9 )、TRAP和活化 T 细胞的核因子、细胞质 1 ( NFATc1 )）。使用蛋白质印迹的机制研究表明 Tet 抑制核因子 (NF) -κ乙通过减少NF-的抑制剂的磷酸化信号传导途径κ乙α（I κ乙α）和p65，它在破骨细胞形成中发挥重要作用。总的来说，我们的数据表明 Tet 抑制了 Ti 诱导的小鼠炎症性骨溶解和破骨细胞的形成，表明 Tet 有可能被开发用于治疗和预防磨损颗粒诱导的炎症性骨溶解。