Li Junhong, Yu Guihua, He Zhiyong, Huang Hui, Yang Jun, Nie Mingbo
Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Department of Orthopedics, Ezhou Central Hospital, Ezhou City 436000, China.
Int Immunopharmacol. 2025 Feb 6;147:114022. doi: 10.1016/j.intimp.2025.114022. Epub 2025 Jan 6.
Osteoarthritis (OA) is the most prevalent joint disorder globally, causing a substantial and increasing socioeconomic burden. Kojic acid (KA) presented potential biological roles in regulating inflammation and autophagy, which was implicated in OA progression. However, its role in chondrocytes and OA has not been reported. To do so, this study aims to explore the chondroprotective effect of KA and elucidate its regulatory mechanisms.
IL-1β in vitro was used to induce OA-like phenotypes. Cell viability was measured by cell counting kit-8 assay. RT-qPCR, western blotting, as well as immunofluorescence staining were used to assess protein and RNA expression of inflammatory (COX2 and iNOS), catabolic (MMP13 and MMP3), anabolic (collagen II, aggrecan and SOX9), and signaling pathways factors. Destabilized medial meniscus (DMM) surgery was adopted to build OA model in vivo. After consecutive 8 weeks of intra-articular injection of KA, X-ray, μ-CT, histological staining, as well as immunohistochemistry staining were adopted to evaluate effects of KA on articular cartilage in vivo.
KA did not affect chondrocyte viability. KA notably elevated anabolic factors expression, simultaneously, inhibited catabolic and inflammatory factors expression in vitro. Mechanistically, KA significantly suppressed the activated NF-κB and PI3K/AKT/mTOR signaling pathways. Moreover, impaired autophagy was restored by KA. Inhibition of autophagy by 3-MA diminished the chondroprotective effect of KA. Intra-articular injection of KA can significantly alleviate DMM-induced cartilage damage in vivo.
Collectively, our work is the first to demonstrate that KA can alleviate osteoarthritis by attenuatinginflammationand restoring impaired autophagy through regulating relevant signaling pathways. This in vivo and in vitro study provides strong evidence supportingKA as a novel and valuable approach for treating OA.
骨关节炎（OA）是全球最常见的关节疾病，造成了巨大且不断增加的社会经济负担。曲酸（KA）在调节炎症和自噬方面具有潜在的生物学作用，而这与OA的进展有关。然而，其在软骨细胞和OA中的作用尚未见报道。为此，本研究旨在探讨KA的软骨保护作用并阐明其调控机制。
体外使用白细胞介素-1β（IL-1β）诱导OA样表型。采用细胞计数试剂盒-8法检测细胞活力。逆转录-定量聚合酶链反应（RT-qPCR）、蛋白质印迹法以及免疫荧光染色用于评估炎症（环氧化酶2（COX2）和诱导型一氧化氮合酶（iNOS））、分解代谢（基质金属蛋白酶13（MMP13）和基质金属蛋白酶3（MMP3））、合成代谢（胶原蛋白II、聚集蛋白聚糖和性别决定区Y框蛋白9（SOX9））以及信号通路因子的蛋白质和RNA表达。采用内侧半月板不稳定（DMM）手术在体内建立OA模型。连续8周关节内注射KA后，采用X射线、显微计算机断层扫描（μ-CT）、组织学染色以及免疫组织化学染色评估KA对体内关节软骨的影响。
KA不影响软骨细胞活力。KA显著提高了体外合成代谢因子的表达，同时抑制了分解代谢和炎症因子的表达。机制上，KA显著抑制了激活的核因子κB（NF-κB）和磷脂酰肌醇-3激酶/蛋白激酶B/哺乳动物雷帕霉素靶蛋白（PI3K/AKT/mTOR）信号通路。此外，KA恢复了受损的自噬。3-甲基腺嘌呤（3-MA）抑制自噬减弱了KA的软骨保护作用。关节内注射KA可显著减轻DMM诱导的体内软骨损伤。
总体而言，我们的研究首次证明KA可通过调节相关信号通路减轻炎症和恢复受损的自噬来缓解骨关节炎。这项体内和体外研究提供了有力证据，支持KA作为一种治疗OA的新的有价值方法。
