Li Xiang, Zhou Ya, Chen Xuefeng, Wang Hongjun, Yang Shuang, Yang Jun, Song Yunfeng, Zhao Zhehui, Zhang Haijing, Wu Lianqiu
State Key Laboratory of Digestive Health, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Tide Pharmaceutical Co., Ltd., Beijing 100176, China.
Acta Pharm Sin B. 2024 Aug;14(8):3528-3542. doi: 10.1016/j.apsb.2024.05.016. Epub 2024 May 18.
Osteoarthritis (OA) is an aging-associated disease characterized by joint stiffness pain and destroyed articular cartilage. Traditional treatments for OA are limited to alleviating various OA symptoms. There is a lack of drugs available in clinical practice that can truly repair cartilage damage. Here, we developed the chondroitin sulfate analog CS-semi5, semi-synthesized from chondroitin sulfate A. , CS-semi5 alleviated inflammation, provided analgesic effects, and protected cartilage in the modified Hulth OA rat model and papain-induced OA rat model. A bioinformatics analysis was performed on samples from OA patients and an exosome analysis on papain-induced OA rats, revealing miR-122-5p as the key regulator associated with CS-semi5 in OA treatment. Binding prediction revealed that miR-122-5p acted on the 3'-untranslated region of p38 mitogen-activated protein kinase, which was related to MMP13 regulation. Subsequent experiments revealed that CS-semi5 effectively reduced cartilage degeneration and maintained matrix homeostasis by inhibiting matrix breakdown through the miR-122-5p/p38/MMP13 axis, which was further validated in the articular cartilage of OA rats. This is the first study to investigate the semi-synthesized chondroitin sulfate CS-semi5, revealing its cartilage-protecting, anti-inflammatory, and analgesic properties that show promising therapeutic effects in OA the miR-122-5p/p38/MMP13 pathway.
骨关节炎（OA）是一种与衰老相关的疾病，其特征为关节僵硬、疼痛和关节软骨破坏。OA的传统治疗方法仅限于缓解各种OA症状。临床实践中缺乏能够真正修复软骨损伤的药物。在此，我们开发了硫酸软骨素类似物CS-semi5，它是由硫酸软骨素A半合成而来。在改良的Hulth OA大鼠模型和木瓜蛋白酶诱导的OA大鼠模型中，CS-semi5减轻了炎症，具有镇痛作用，并保护了软骨。对OA患者的样本进行了生物信息学分析，对木瓜蛋白酶诱导的OA大鼠进行了外泌体分析，结果显示miR-122-5p是OA治疗中与CS-semi5相关的关键调节因子。结合预测表明，miR-122-5p作用于p38丝裂原活化蛋白激酶的3'-非翻译区，这与MMP13的调节有关。随后的实验表明，CS-semi5通过miR-122-5p/p38/MMP13轴抑制基质分解，有效减少了软骨退变并维持了基质稳态，这在OA大鼠的关节软骨中得到了进一步验证。这是第一项研究半合成硫酸软骨素CS-semi5的研究，揭示了其软骨保护、抗炎和镇痛特性，这些特性在OA中通过miR-122-5p/p38/MMP13途径显示出有前景的治疗效果。
