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The disorders of cartilage homeostasis and chondrocyte apoptosis are major events in the pathogenesis of osteoarthritis (OA). Herein, we aim to assess the chondroprotective effect and underlying mechanisms of a novel chemically modified curcumin, CMC2.24, in modulating extracellular matrix (ECM) homeostasis and inhibiting chondrocyte apoptosis. Rats underwent the anterior cruciate ligament transection, and medial menisci resection was treated by intra-articular injection with CMC2.24. In an in vitro study, rat chondrocytes were pretreated with CMC2.24 before stimulation with sodium nitroprusside (SNP). Results from in vivo studies demonstrated that the intra-articular administration of CMC2.24 ameliorated osteoarthritic cartilage destruction by promoting collagen 2a1 production and inhibited cartilage degradation and apoptosis by suppressing hypoxia-inducible factor-2a (Hif-2α), matrix metalloproteinase-3, runt-related transcription factor 2, cleaved caspase-3, and vascular endothelial growth factor and the phosphorylation of IκBα and NF-κB p65. The in vitro results revealed that CMC2.24 exhibited a strong inhibitory effect on SNP-induced chondrocyte catabolism and apoptosis. The SNP-enhanced expression of Hif-2α, a catabolic and apoptotic factor, decreased in a dose-dependent manner after CMC2.24 treatment. CMC2.24 pretreatment effectively inhibited SNP-induced IκBα and NF-κB p65 phosphorylation in rat chondrocytes, whereas pretreatment with the NF-κB antagonist BMS-345541 significantly enhanced the effects of CMC2.24. Overall, these results demonstrated that CMC2.24 attenuates OA progression by modulating ECM homeostasis and chondrocyte apoptosis by suppressing the NF-κB/Hif-2α axis, thus providing a new perspective for therapeutic strategies in OA. KEY MESSAGES: • Intra-articular injection of CMC2.24 ameliorated osteoarthritic cartilage destruction. • CMC2.24 promoted cell viability and decreased SNP-induced apoptotic gene expression. • SNP-induced activation of Hif-2α is inhibited by CMC2.24. • CMC2.24 inhibits NF-κB/Hif-2α axis activation to modulate ECM homeostasis and inhibit chondrocyte apoptosis.

软骨稳态和软骨细胞凋亡紊乱是骨关节炎（OA）发病机制中的主要事件。在此，我们旨在评估新型化学修饰姜黄素 CMC2.24 对细胞外基质（ECM）稳态的调节和抑制软骨细胞凋亡的软骨保护作用及其潜在机制。大鼠接受前交叉韧带横断和内侧半月板切除术，并通过关节内注射 CMC2.24 进行治疗。在体外研究中，大鼠软骨细胞在受到硝普钠（SNP）刺激前用 CMC2.24 预处理。体内研究结果表明，关节内给予 CMC2.24 通过促进胶原 2a1 的产生来改善 OA 软骨破坏，并通过抑制缺氧诱导因子-2a（Hif-2α）、基质金属蛋白酶-3、Runt 相关转录因子 2、裂解 caspase-3、血管内皮生长因子和 IκBα 和 NF-κB p65 的磷酸化来抑制软骨降解和凋亡。体外结果表明，CMC2.24 对 SNP 诱导的软骨细胞分解代谢和凋亡具有很强的抑制作用。SNP 增强的分解代谢和凋亡因子 Hif-2α 的表达在 CMC2.24 处理后呈剂量依赖性降低。CMC2.24 预处理可有效抑制 SNP 诱导的大鼠软骨细胞 IκBα 和 NF-κB p65 磷酸化，而 NF-κB 拮抗剂 BMS-345541 的预处理可显著增强 CMC2.24 的作用。总体而言，这些结果表明，CMC2.24 通过抑制 NF-κB/Hif-2α 轴来调节 ECM 稳态和软骨细胞凋亡，从而减轻 OA 进展，为 OA 的治疗策略提供了新视角。