Department of Orthopedic Surgery, Shengjing Hospital of China Medical University, Shenyang 110000, China.
Department of Ultrasound, Shengjing Hospital, China Medical University, Shenyang, Liaoning, China.
Biomed Pharmacother. 2022 Sep;153:113361. doi: 10.1016/j.biopha.2022.113361. Epub 2022 Jul 4.
Our previous study found that lipoxin A (LXA) exerts therapeutic effects on osteoarthritis (OA). In this study, we evaluated the effects of LXA via synovial macrophage M1/M2 subtype polarization on chondrocyte pyroptosis and corresponding mechanisms during mechanical stimulation. Synovial macrophages were subjected to various LXA concentrations and cyclic tensile strain (CTS) conditions to determine optimal co-culture conditions. The effects of LXA on chondrocyte pyroptosis, as represented by macrophage M1/M2 subtype polarization, were detected by western blot, immunofluorescence, and flow cytometry analyses. Forty male Sprague-Dawley rats were randomly divided into four groups (n = 10): control (CG), OA (OAG), OA with moderate-intensity treadmill exercise (OAE), and OAE + BOC-2 (an LXA antagonist). All rats were evaluated using histology, enzyme-linked immunosorbent assay, quantitative real-time polymerase chain reaction, and western blot analyses. We found that with increasing Kellgren-Lawrence grade, LXA expression was downregulated in articular fluid and that CD86 and Arg1 expression was upregulated in the synovium of patients. In vitro, CTS and LXA both promoted M2 subtype polarization of synovial macrophages, which inhibited the nuclear translocation of NF-κB p65 and formation of NLRP3 in chondrocytes. In vivo, the OAE treatment exerted protective effects on articular cartilage and facilitated M2 polarization of synovial macrophages. These effects were suppressed by BOC-2 treatment. We concluded that moderate CTS enhances therapeutic effects of LXA by inhibiting the nuclear translocation of NF-κB p65 and NLRP3. Furthermore, the therapeutic effects of LXA during treadmill exercise in monoiodoacetate-induced OA were driven by promotion of synovial macrophage M2 subtype polarization.
我们之前的研究发现脂氧素 A（LXA）对骨关节炎（OA）具有治疗作用。在这项研究中，我们评估了 LXA 通过滑膜巨噬细胞 M1/M2 亚型极化对机械刺激下软骨细胞焦亡的影响及其相应机制。滑膜巨噬细胞接受不同浓度的 LXA 和循环拉伸应变（CTS）条件，以确定最佳共培养条件。通过 Western blot、免疫荧光和流式细胞术分析检测 LXA 对软骨细胞焦亡的影响，以巨噬细胞 M1/M2 亚型极化来表示。40 只雄性 Sprague-Dawley 大鼠随机分为四组（n=10）：对照组（CG）、OA 组（OAG）、OA 中强度跑步机运动组（OAE）和 OAE+BOC-2（LXA 拮抗剂）组。所有大鼠均进行组织学、酶联免疫吸附试验、实时定量聚合酶链反应和 Western blot 分析。我们发现，随着 Kellgren-Lawrence 分级的增加，关节液中 LXA 的表达下调，滑膜中 CD86 和 Arg1 的表达上调。在体外，CTS 和 LXA 均促进滑膜巨噬细胞向 M2 亚型极化，抑制 NF-κB p65 核转位和 NLRP3 在软骨细胞中的形成。在体内，OAE 治疗对关节软骨具有保护作用，并促进滑膜巨噬细胞向 M2 极化。BOC-2 治疗抑制了这些作用。我们得出结论，适度 CTS 通过抑制 NF-κB p65 和 NLRP3 的核转位增强 LXA 的治疗作用。此外，LXA 在单碘乙酸诱导的 OA 跑步机运动中的治疗作用是通过促进滑膜巨噬细胞 M2 亚型极化来驱动的。
