Zhou Xuchang, Yang Yajing, Qiu Xu, Deng Huili, Cao Hong, Liao Tao, Chen Xier, Huang Caihua, Lin Donghai, Ni Guoxin
Department of Rehabilitation Medicine, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361003, China.
Department of Acupuncture and Moxibustion, Hubei University of Chinese Medicine, Wuhan 430070, China.
J Adv Res. 2025 Jan 6. doi: 10.1016/j.jare.2025.01.010.
The aim of this study was to investigate the potential molecular mechanisms by which taurine protects against cartilage degeneration.
The anterior cruciate ligament transection (ACLT) surgery was used to construct an animal model of osteoarthritis (OA). Metabolomics was used to identify characteristic metabolites in osteoarthritic chondrocytes. Transcriptomics and metabolomics were used to explore potential mechanisms by which the small molecule metabolite taurine protects against inflammatory chondrocyte damage. Cell transfection and small molecule inhibitors/agonists were used to validate the molecular mechanisms by which taurine protects inflammatory chondrocytes in vitro. Finally, adeno-associated virus and small molecule inhibitors/agonists were used to validate the molecular mechanisms by which taurine protects against cartilage degeneration in vivo.
Metabolomic assays identified taurine as a possible key metabolic molecule in the progression of OA. Transcriptomics and metabolomics revealed that O-GlcNAc transferase (OGT)-dependent O-GlcNAcylation and Gpx4-dependent ferroptosis may mediate the inflammatory protective effects of taurine on chondrocytes, which was further confirmed by gain and loss of function in vitro. Subsequently, further experiments indicated that the possible existence of a direct binding site for Gpx4 and OGT proteins, which provides evidence for the presence of O-GlcNAc modification of Gpx4 protein. Finnaly, we demonstrated that Gpx4-dependent ferroptosis and OGT-dependent O-GlcNAcylation may be potential mechanisms by which taurine protects against cartilage degeneration in vivo.
Antioxidant taurine inhibits chondrocyte ferroptosis through upregulation of OGT/Gpx4 signaling. Supplementation with taurine, a safe nonessential amino acid, may be a potential therapeutic strategy for OA.
本研究旨在探讨牛磺酸预防软骨退变的潜在分子机制。
采用前交叉韧带横断术（ACLT）构建骨关节炎（OA）动物模型。代谢组学用于鉴定骨关节炎软骨细胞中的特征性代谢物。转录组学和代谢组学用于探索小分子代谢物牛磺酸预防炎性软骨细胞损伤的潜在机制。细胞转染和小分子抑制剂/激动剂用于在体外验证牛磺酸保护炎性软骨细胞的分子机制。最后，腺相关病毒和小分子抑制剂/激动剂用于在体内验证牛磺酸预防软骨退变的分子机制。
代谢组学分析确定牛磺酸是OA进展中可能的关键代谢分子。转录组学和代谢组学显示，O-连接的N-乙酰葡糖胺转移酶（OGT）依赖性O-GlcNAc糖基化和谷胱甘肽过氧化物酶4（Gpx4）依赖性铁死亡可能介导牛磺酸对软骨细胞的炎性保护作用，这在体外功能获得和缺失实验中得到进一步证实。随后，进一步实验表明Gpx4和OGT蛋白可能存在直接结合位点，这为Gpx4蛋白存在O-GlcNAc修饰提供了证据。最后，我们证明Gpx4依赖性铁死亡和OGT依赖性O-GlcNAc糖基化可能是牛磺酸在体内预防软骨退变的潜在机制。
抗氧化剂牛磺酸通过上调OGT/Gpx4信号通路抑制软骨细胞铁死亡。补充牛磺酸这种安全的非必需氨基酸可能是OA的一种潜在治疗策略。
