Zhang Baolin, Xiao Ya, Su Deying, Li Chuan, Zhang Shun, Long Jiahui, Weng Ricong, Liu Hengyu, Chen Yingtong, Liao Zhiheng, Zhu Xu, Huang Junming, Chen Shuqing, Zhou Taifeng, Ma Yuan, Xu Caixia
Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Department of Spine Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China.
Research Center for Translational Medicine, First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510006, China.
Phytomedicine. 2025 Jan;136:156329. doi: 10.1016/j.phymed.2024.156329. Epub 2024 Dec 15.
Osteoarthritis (OA) is characterized by the progressive deterioration of articular cartilage, leading to joint pain and functional impairment. OA severely impacts quality of life and presents a substantial societal burden. Currently, effective treatment options remain limited. Morinda officinalis (MO), a traditional Chinese herb, is commonly used to treat rheumatoid arthritis and alleviate joint pain. M13, an anthraquinone extracted from MO, has shown significant anti-inflammatory properties, making it a promising candidate for the treatment of OA. However, its role in inhibiting OA progression and the mechanisms involved remain poorly understood.
The objective of this study is to examine the impact of M13 on osteoarthritis and uncover the mechanisms.
The effects of M13 on OA were assessed using TNF-α induced chondrocyte models and mice with destabilization of the medial meniscus (DMM). Celecoxib was used as a positive control. We evaluated the expression of factors related to chondrocyte degeneration and inflammation through qRT-PCR, immunoblotting, and immunofluorescence. Chondrocyte viability was measured using CCK-8 assays, EdU staining, and flow cytometry. Molecular docking, molecular dynamics simulations and isothermal titration calorimetry (ITC) were performed to evaluate the binding efficacy of target proteins. Additionally, the therapeutic effects of M13 in OA mice were confirmed through in vivo experiments.
In primary murine chondrocytes, M13 rescued TNF-α-induced matrix degradation and loss of vitality while suppressing ROS generation. Mechanistically, STAT3 was identified as a target protein of M13, through which M13 mitigated OA by inhibiting the STAT3 signaling pathway. Further in vivo experiments demonstrated that M13 reduced the scores of the Osteoarthritis Research Society International (OARSI), alleviating cartilage impairment. M13 enhanced levels of collagen II and aggrecan in cartilage tissue while decreasing the amounts of cartilage-degrading proteins ADAMTS-5 and MMP13.
This is the first study to validate that M13 mitigates the inflammation and damage in cartilage tissue by blocking the STAT3 signaling pathway. These findings hold promise for enhancing innovative clinical interventions targeting OA.
骨关节炎（OA）的特征是关节软骨进行性退变，导致关节疼痛和功能障碍。OA严重影响生活质量并带来巨大的社会负担。目前，有效的治疗选择仍然有限。巴戟天（MO）是一种传统中药，常用于治疗类风湿性关节炎和缓解关节疼痛。从MO中提取的蒽醌M13已显示出显著的抗炎特性，使其成为治疗OA的有前景的候选药物。然而，其在抑制OA进展中的作用及相关机制仍知之甚少。
本研究的目的是研究M13对骨关节炎的影响并揭示其机制。
使用肿瘤坏死因子-α（TNF-α）诱导的软骨细胞模型和内侧半月板不稳定（DMM）小鼠评估M13对OA的作用。塞来昔布用作阳性对照。通过定量逆转录聚合酶链反应（qRT-PCR）、免疫印迹和免疫荧光评估与软骨细胞退变和炎症相关的因子表达。使用细胞计数试剂盒-8（CCK-8）检测、5-乙炔基-2'-脱氧尿苷（EdU）染色和流式细胞术测量软骨细胞活力。进行分子对接、分子动力学模拟和等温滴定量热法（ITC）以评估靶蛋白的结合效力。此外，通过体内实验证实M13对OA小鼠的治疗效果。
在原代小鼠软骨细胞中，M13挽救了TNF-α诱导的基质降解和活力丧失，同时抑制了活性氧（ROS）生成。机制上，信号转导和转录激活因子3（STAT3）被鉴定为M13的靶蛋白，M13通过抑制STAT3信号通路减轻OA。进一步的体内实验表明，M13降低了国际骨关节炎研究学会（OARSI）评分，减轻了软骨损伤。M13提高了软骨组织中II型胶原蛋白和聚集蛋白聚糖的水平，同时减少了软骨降解蛋白含血小板反应蛋白基序的解聚素样金属蛋白酶-5（ADAMTS-5）和基质金属蛋白酶13（MMP13）的量。
这是第一项验证M13通过阻断STAT3信号通路减轻软骨组织炎症和损伤的研究。这些发现有望加强针对OA的创新临床干预措施。
