Department of Rheumatology and Immunology, Afliated Hospital of Zunyi Medical University, Huichuan District, 149 Dalian Road, Zunyi 563000, China; Department of Nephrology and Rheumatology, Guizhou Moutai Hospital, Renhuai 564500, China.
Department of Rheumatology and Immunology, Afliated Hospital of Zunyi Medical University, Huichuan District, 149 Dalian Road, Zunyi 563000, China.
Int Immunopharmacol. 2024 May 30;133:112010. doi: 10.1016/j.intimp.2024.112010. Epub 2024 Apr 17.
Chondrocyte ferroptosis plays a critical role in the pathogenesis of osteoarthritis (OA), regulated by the SLC7A11/GPX4 signaling pathway. Icariin (ICA), a flavonoid glycoside, exhibits strong anti-inflammatory and antioxidant activities. This study investigated whether ICA could modulate the SLC7A11/GPX4 signaling to inhibit chondrocyte ferroptosis and alleviate OA.
The objective was to explore the impact of ICA on chondrocyte ferroptosis in OA and its modulation of the SLC7A11/GPX4 signaling pathway.
The anti-ferroptosis effects of ICA were evaluated in an interleukin-1β (IL-1β)-treated SW1353 cell model, using Ferrostatin-1 (Fer-1) and Erastin (Era) as ferroptosis inhibitor and inducer, respectively, along with GPX4 knockdown via lentivirus-based shRNA. Additionally, the therapeutic efficacy of ICA on OA-related articular cartilage damage was assessed in rats through histopathology and immunohistochemistry (IHC).
IL-1β treatment upregulated the expression of OA-associated matrix metalloproteinases (MMP3 and MMP1), a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS-5), and increased intracellular ROS, lipid ROS, and MDA levels while downregulating collagen II and SOX9 expression in SW1353 cells. ICA treatment countered the IL-1β-induced upregulation of MMPs and ADAMTS-5, restored collagen II and SOX9 expression, and reduced intracellular ROS, lipid ROS, and MDA levels. Furthermore, IL-1β upregulated P53 but downregulated SLC7A11 and GPX4 expression in SW1353 cells, effects that were mitigated by ICA or Fer-1 treatment. Significantly, ICA also alleviated Era-induced ferroptosis, whereas it had no effect on GPX4-silenced SW1353 cells. In vivo, ICA treatment reduced articular cartilage damage in OA rats by partially restoring collagen II and GPX4 expression, inhibiting cartilage extracellular matrix (ECM) degradation and chondrocyte ferroptosis.
ICA treatment mitigated chondrocyte ferroptosis and articular cartilage damage by enhancing the SLC7A11/GPX4 signaling, suggesting its potential as a therapeutic agent for OA interventions.
软骨细胞铁死亡在骨关节炎（OA）的发病机制中起着关键作用，受 SLC7A11/GPX4 信号通路调控。淫羊藿苷（ICA）是一种黄酮类糖苷，具有很强的抗炎和抗氧化活性。本研究探讨了 ICA 是否能调节 SLC7A11/GPX4 信号抑制软骨细胞铁死亡，从而缓解 OA。
探讨 ICA 对 OA 中软骨细胞铁死亡的影响及其对 SLC7A11/GPX4 信号通路的调节作用。
用白细胞介素-1β（IL-1β）处理的 SW1353 细胞模型评估 ICA 的抗铁死亡作用，分别用 Ferrostatine-1（Fer-1）和 Erastin（Era）作为铁死亡抑制剂和诱导剂，并用基于慢病毒的 shRNA 敲低 GPX4。此外，通过组织病理学和免疫组织化学（IHC）评估 ICA 对大鼠 OA 相关关节软骨损伤的治疗效果。
IL-1β 处理上调了与 OA 相关的基质金属蛋白酶（MMP3 和 MMP1）、解整合素和金属蛋白酶与血栓反应蛋白基序（ADAMTS-5）的表达，增加了细胞内 ROS、脂质 ROS 和 MDA 水平，同时下调了 SW1353 细胞中胶原蛋白 II 和 SOX9 的表达。ICA 处理抑制了 IL-1β 诱导的 MMPs 和 ADAMTS-5 的上调，恢复了胶原蛋白 II 和 SOX9 的表达，并降低了细胞内 ROS、脂质 ROS 和 MDA 水平。此外，IL-1β 上调了 SW1353 细胞中的 P53，但下调了 SLC7A11 和 GPX4 的表达，ICA 或 Fer-1 处理减轻了这种作用。值得注意的是，ICA 还减轻了 Era 诱导的铁死亡，而对 GPX4 沉默的 SW1353 细胞没有影响。体内，ICA 治疗通过部分恢复胶原蛋白 II 和 GPX4 的表达，抑制软骨细胞外基质（ECM）降解和软骨细胞铁死亡，减轻 OA 大鼠的关节软骨损伤。
ICA 通过增强 SLC7A11/GPX4 信号减轻软骨细胞铁死亡和关节软骨损伤，表明其在 OA 干预中的治疗潜力。
