ABSTRACT

Aims

Inflammatory responses to wear debris cause osteolysis that leads to aseptic loosening and hip arthroplasty failure. Wear debris stimulate macrophages and fibroblasts to secret proinflammatory cytokines, including TNF-α and IL-6, which have been specifically implicated in periprosthetic osteolysis and osteoclast differentiation. Naringin has anti-inflammatory effect in macrophages. Moreover, naringin inhibited osteoclastogenesis and wear particles-induced osteolysis. In this study, we examined the potential inhibitory effects of naringin on titanium (Ti) particle-induced proinflammatory cytokines secretion in fibroblasts and the possible underlying molecular mechanisms.

Materials and methods

Fibroblasts were isolated from periprosthetic membrane at the time of revision surgery performed due to aseptic loosening after hip arthroplasty and were cultured in the presence or absence of Ti particles, naringin and mitogen-activated protein kinase (MAPK) inhibitors, PD98059 (a selective inhibitor of ERK), SP600125 (a selective inhibitor of JNK), and SB203580 (a selective inhibitor of p38). TNF-α and IL-6 assays were performed using enzyme-linked immunosorbent assay kits. The phosphorylation levels of p38 and nuclear factor kappa B p65 (NF-κB p65) were examined by western blot.

Results

Naringin or SB203580 pretreatment significantly suppressed the secretion of TNF-α and IL-6 induced by titanium particles in fibroblasts, while inhibition of ERK or JNK pathways showed no effect on production of TNF-α and IL-6. Moreover, naringin inhibited Ti particle-induced phosphorylation of p38 and p65.

Conclusions

These results indicated that naringin could inhibit Ti particle-induced inflammation in fibroblasts by inhibiting p38 MAPK/NF-κB p65 activity and might be a potential drug for the treatment of inflammatory periprosthetic osteolysis after arthroplasty.

中文翻译：

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柚皮苷通过 p38 MAPK 通路抑制钛颗粒诱导的髋关节假体周围膜成纤维细胞中 TNF-α 和 IL-6 的上调

摘要

目标

对磨损碎片的炎症反应导致骨质溶解，导致无菌性松动和髋关节置换术失败。磨损碎片刺激巨噬细胞和成纤维细胞分泌促炎细胞因子，包括 TNF-α 和 IL-6，这些细胞因子与假体周围骨质溶解和破骨细胞分化密切相关。柚皮苷在巨噬细胞中具有抗炎作用。此外，柚皮苷抑制破骨细胞生成和磨损颗粒诱导的骨质溶解。在这项研究中，我们检查了柚皮苷对钛 (Ti) 颗粒诱导的成纤维细胞中促炎细胞因子分泌的潜在抑制作用以及可能的潜在分子机制。

材料和方法

由于髋关节置换术后无菌性松动，在进行翻修手术时从假体周围膜分离成纤维细胞，并在存在或不存在 Ti 颗粒、柚皮苷和丝裂原活化蛋白激酶 (MAPK) 抑制剂 PD98059（一种选择性抑制剂ERK）、SP600125（JNK 的选择性抑制剂）和 SB203580（p38 的选择性抑制剂）。使用酶联免疫吸附测定试剂盒进行 TNF-α 和 IL-6 测定。通过蛋白质印迹检查 p38 和核因子 kappa B p65 (NF-κB p65) 的磷酸化水平。

结果

柚皮苷或 SB203580 预处理显着抑制钛颗粒诱导的成纤维细胞中 TNF-α 和 IL-6 的分泌，而抑制 ERK 或 JNK 通路对 TNF-α 和 IL-6 的产生没有影响。此外，柚皮苷抑制钛颗粒诱导的 p38 和 p65 磷酸化。

结论

这些结果表明柚皮苷可通过抑制 p38 MAPK/NF-κB p65 活性来抑制 Ti 颗粒诱导的成纤维细胞炎症，可能是治疗关节置换术后炎症性假体周围骨溶解的潜在药物。