Objective

NLRP3 inflammasome may play a key role in OA pathogenesis. Stromal cell-derived factor-1 (SDF-1) is a homeostatic CXC chemokine. Since the role of SDF-1 in OA has not been explored, this study aimed to examine the effect of SDF-1 on NLRP3 inflammasome and pyroptosis in synoviocytes from OA joints.

Materials and methods

Human synovium was obtained from OA patients for isolation of primary synoviocytes and a murine model of collagenase-induced OA was established for testing intra-articular injections of SDF-1. Immunoblotting assays were used to examine the effects and underlying mechanism of action of SDF-1 on NLRP3 inflammasome and synoviocyte pyroptosis in synoviocytes. Inhibitors of AMPK and PI3K–mTOR were utilized to investigate the key signaling pathways involved in SDF-1-mediated OA inflammasome formation and pyroptosis.

Results

Synoviocytes from OA joints exhibited significantly higher expression of NLRP3 inflammasome and biomarkers of synoviocyte pyroptosis relative to healthy individuals. This was confirmed in the collagenase-induced OA model, where OA synoviocytes had a significantly lower SDF-1 expression than healthy ones. SDF-1 treatment in synoviocytes of OA patients and collagenase-induced OA led to significant downregulation in the expression of NLRP3 inflammasome and synoviocyte pyroptosis biomarkers. Inhibition of the AMPK signaling pathway significantly suppressed the inhibitory effect of SDF-1 on NLRP3 inflammasome expression of OA synoviocytes. However, blocking the SDF-1-activated PI3K–mTOR signaling pathway could still suppress the expression of NLRP3 inflammasome and synoviocyte pyroptosis biomarkers.

Conclusions

SDF-1 ameliorates NLRP3 inflammasome and pyroptosis in OA synoviocytes through activation of the AMPK signaling pathway. Therefore, SDF-1 may be a novel therapeutic target for OA.

中文翻译：

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外源性基质细胞衍生因子-1 (SDF-1) 通过激活 AMPK 信号通路抑制 NLRP3 炎性体并抑制骨关节炎关节滑膜细胞的焦亡

客观的

NLRP3 炎症小体可能在 OA 发病机制中起关键作用。基质细胞衍生因子-1 (SDF-1) 是一种稳态 CXC 趋化因子。由于尚未探索 SDF-1 在 OA 中的作用，本研究旨在检查 SDF-1 对 OA 关节滑膜细胞中 NLRP3 炎症小体和细胞焦亡的影响。

材料和方法

从 OA 患者获得人类滑膜用于分离原代滑膜细胞，并建立了胶原酶诱导的 OA 小鼠模型用于测试 SDF-1 的关节内注射。免疫印迹分析用于检查 SDF-1 对滑膜细胞中 NLRP3 炎性体和滑膜细胞焦亡的影响和潜在作用机制。AMPK 和 PI3K-mTOR 抑制剂被用来研究参与 SDF-1 介导的 OA 炎性体形成和细胞焦亡的关键信号通路。

结果

与健康个体相比，来自 OA 关节的滑膜细胞表现出显着更高的 NLRP3 炎性体表达和滑膜细胞焦亡的生物标志物。这在胶原酶诱导的 OA 模型中得到证实，其中 OA 滑膜细胞的 SDF-1 表达明显低于健康细胞。OA 患者滑膜细胞中的 SDF-1 治疗和胶原酶诱导的 OA 导致 NLRP3 炎症小体和滑膜细胞焦亡生物标志物的表达显着下调。AMPK信号通路的抑制显着抑制了SDF-1对OA滑膜细胞NLRP3炎性体表达的抑制作用。然而，阻断 SDF-1 激活的 PI3K-mTOR 信号通路仍然可以抑制 NLRP3 炎症小体和滑膜细胞焦亡生物标志物的表达。

结论

SDF-1 通过激活 AMPK 信号通路改善 OA 滑膜细胞中的 NLRP3 炎症小体和细胞焦亡。因此，SDF-1 可能是 OA 的新治疗靶点。