Department of Rheumatology, The First Affiliated Hospital of Harbin Medical University, No. 23 Youzheng St, Harbin, 150001, China.
Department of Joint Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Guangdong, China.
Inflammopharmacology. 2021 Jun;29(3):695-704. doi: 10.1007/s10787-021-00814-x. Epub 2021 Jun 3.
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.
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.
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.
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.
NLRP3 炎性小体可能在 OA 发病机制中发挥关键作用。基质细胞衍生因子-1（SDF-1）是一种稳态 CXC 趋化因子。由于 SDF-1 在 OA 中的作用尚未得到探索，本研究旨在研究 SDF-1 对 OA 关节滑膜细胞中 NLRP3 炎性小体和细胞焦亡的影响。
从 OA 患者中获得人滑膜组织，用于分离原代滑膜细胞，并建立胶原酶诱导的 OA 模型，以测试 SDF-1 的关节内注射。免疫印迹法用于研究 SDF-1 对 NLRP3 炎性小体和滑膜细胞焦亡的作用及其作用机制。使用 AMPK 和 PI3K-mTOR 抑制剂来研究 SDF-1 介导的 OA 炎性小体形成和细胞焦亡中涉及的关键信号通路。
与健康个体相比，OA 关节的滑膜细胞中 NLRP3 炎性小体和滑膜细胞细胞焦亡的生物标志物表达明显升高。在胶原酶诱导的 OA 模型中得到了证实，OA 滑膜细胞的 SDF-1 表达明显低于健康者。SDF-1 处理 OA 患者和胶原酶诱导的 OA 滑膜细胞可显著下调 NLRP3 炎性小体和滑膜细胞细胞焦亡的生物标志物表达。抑制 AMPK 信号通路显著抑制 SDF-1 对 OA 滑膜细胞 NLRP3 炎性小体表达的抑制作用。然而，阻断 SDF-1 激活的 PI3K-mTOR 信号通路仍可抑制 NLRP3 炎性小体和滑膜细胞细胞焦亡的生物标志物表达。
SDF-1 通过激活 AMPK 信号通路改善 OA 滑膜细胞中的 NLRP3 炎性小体和细胞焦亡。因此，SDF-1 可能是 OA 的一种新的治疗靶点。
