Dai Mengyuan, Shi Jing, Wang Tao, Wan Sha, Fan Chen, Wang Siyu, Chen Siyuan, Shang Jiaojiao, Kong Qingquan
State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, Center for Immunology and Hematology and General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu, China.
Science and Education Section, Hospital of Chengdu Office of People's Government of Xizang Autonomous Region (Hospital.C.X.), Chengdu, Sichuan, China.
Front Pharmacol. 2025 Aug 13;16:1624818. doi: 10.3389/fphar.2025.1624818. eCollection 2025.
Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage erosion, subchondral bone remodeling, and synovial inflammation. OA progression is driven by an imbalance between anabolic and catabolic activities in the cartilage extracellular matrix (ECM). Identifying molecular targets involved in chondrocyte (responsible for ECM homeostasis in OA) dysfunction is therefore essential for developing effective OA treatments. Notably, epigallocatechin-3-gallate (EGCG), a polyphenolic compound derived from green tea, is a known pan-assay interference compound (PAINS), which may produce non-specific effects (e.g., protein binding, redox interference) that challenge the interpretation of its pharmacological relevance. Thus, multi-dimensional validation ( + + transcriptomic) is critical to mitigate such limitations.
We investigated the effects of epigallocatechin-3-gallate (EGCG), a polyphenolic compound derived from green tea, on OA-induced dysfunction in chondrocytes. Primary chondrocytes, extracted from the knee joints of rats and constructed an OA model via IL-1β stimulation, observed cell viability and morphology upon EGCG treatment. Transcriptomic analysis was conducted to screen for differentially expressed genes. Subsequently, an OA model in rats was induced by intra-articular injection of monoiodoacetic acid (MIA), and EGCG was administered for OA treatment to validate the expression of the differentially expressed genes.
EGCG could reduce reactive oxygen species (ROS) levels and decreased the expression of inflammatory cytokines IL-β, MMP13, and TNF-α. Transcriptome analysis identified differentially expressed genes, and network pharmacology pinpointed Pla2g2a as a key target of EGCG. Molecular docking studies confirmed a strong binding affinity between EGCG and Pla2g2a. OA model demonstrated that EGCG treatment significantly promoted cartilage repair and increased Pla2g2a expression. experiments demonstrated that EGCG treatment significantly promoted cartilage repair and upregulated Pla2g2a expression, consistent with and transcriptomic findings-suggesting the observed effects are not solely due to PAINS interference.
These findings underscore the therapeutic potential of EGCG in OA management via antioxidative, anti-inflammatory properties, and Pla2g2a-mediated modulation. Notably, the consistency across , and transcriptomic data supports the biological relevance of EGCG's effects, despite its PAINS characteristics.
骨关节炎（OA）是一种退行性关节疾病，其特征为软骨侵蚀、软骨下骨重塑和滑膜炎症。OA的进展是由软骨细胞外基质（ECM）中合成代谢与分解代谢活动之间的失衡所驱动的。因此，识别参与软骨细胞（OA中负责ECM稳态）功能障碍的分子靶点对于开发有效的OA治疗方法至关重要。值得注意的是，表没食子儿茶素-3-没食子酸酯（EGCG），一种源自绿茶的多酚化合物，是一种已知的泛分析干扰化合物（PAINS），它可能产生非特异性效应（如蛋白质结合、氧化还原干扰），这对其药理学相关性的解释提出了挑战。因此，多维验证（+转录组学）对于减轻此类局限性至关重要。
我们研究了源自绿茶的多酚化合物表没食子儿茶素-3-没食子酸酯（EGCG）对OA诱导的软骨细胞功能障碍所产生的影响。从大鼠膝关节提取原代软骨细胞，并通过白细胞介素-1β刺激构建OA模型，观察EGCG处理后的细胞活力和形态。进行转录组分析以筛选差异表达基因。随后，通过关节内注射单碘乙酸（MIA）诱导大鼠OA模型，并给予EGCG进行OA治疗，以验证差异表达基因的表达。
EGCG可降低活性氧（ROS）水平，并降低炎性细胞因子白细胞介素-β、基质金属蛋白酶13和肿瘤坏死因子-α的表达。转录组分析确定了差异表达基因，网络药理学将磷脂酶A2G2A（Pla2g2a）确定为EGCG的关键靶点。分子对接研究证实了EGCG与Pla2g2a之间具有很强的结合亲和力。OA模型表明，EGCG治疗显著促进软骨修复并增加Pla2g2a表达。实验表明，EGCG治疗显著促进软骨修复并上调Pla2g2a表达，这与实验和转录组学结果一致，表明观察到的效应并非仅由PAINS干扰所致。
这些发现强调了EGCG通过抗氧化、抗炎特性以及Pla2g2a介导的调节在OA管理中的治疗潜力。值得注意的是，尽管EGCG具有PAINS特征，但实验、实验和转录组数据之间的一致性支持了EGCG效应的生物学相关性。
