Gou Yong, Wang Chenggui, Fu Kejian, Su Shenkai, Zhou Hangjin, Bao Chunkai, Nan Hui, Zhang Xiang, Xu Yiyuan, Chen Qi, Gu Xinchen, Chen Baiting, Zheng Lin, Xie Chenglong, Zhang Man, Xue Enxing, Li Jiawei
Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China.
Key Laboratory of Orthopedics of Zhejiang Province, Wenzhou, 325027, China.
J Orthop Translat. 2025 Mar 19;51:242-255. doi: 10.1016/j.jot.2025.01.012. eCollection 2025 Mar.
The production of reactive oxygen species (ROS) and mitochondrial dysfunction in chondrocytes are closely related to cartilage degeneration in the procedure of osteoarthritis (OA). Mitophagy is responsible for the scavenging of ROS and dysfunctional mitochondria and is considered a key therapeutic target for the treatment of OA. Tiopronin, a classic thiol antioxidant, has been widely studied for the treatment of various oxidative stress-related diseases.
The expression of mitophagy (PINK1, PARKIN, and TOMM20) in intact and damaged cartilage of OA patients was analyzed by Western blot and histological analysis. RNA sequencing (RNA-seq) analysis was performed to explore the molecular mechanism of tiopronin in regulating mitophagy in chondrocytes, and then to find the specific target of tiopronin. The therapeutic effects of tiopronin were evaluated in the OA model induced by destabilisation of the medial meniscus (DMM), chondrocytes degenerative model with the primary chondrocytes from mouse and human cartilage explants experiment. The downstream molecular mechanisms of tiopronin were further investigated by si-RNA knockdown of mitophagy-related proteins.
The level of mitophagy in cartilage was negatively correlated with the severity of OA. We revealed that tiopronin promoted the anabolism of the extracellular matrix (ECM) of hyaline chondrocytes and alleviates ROS and by strengthening mitophagy. Moreover, tiopronin strongly activated the expression of Bnip3, a protein anchored in the mitochondrial membrane, and subsequently enhanced the Pink1/Parkin signaling pathway.
These findings indicate that the Bnip3-Pink1-Parkin signaling pathway, targeted and activated by tiopronin, plays a key role in inhibiting the progression of OA.
As a classical drug in clinic, tiopronin was developed a new therapeutic approach in the treatment in OA via this study. Based the significant and efficient effect of tiopronin in inhibiting the cartilage degermation and delay the progression of OA, it was believed that tiopronin may become an effective therapeutic candidate for OA treatment in clinical settings.
软骨细胞中活性氧（ROS）的产生和线粒体功能障碍与骨关节炎（OA）病程中的软骨退变密切相关。线粒体自噬负责清除ROS和功能失调的线粒体，被认为是治疗OA的关键治疗靶点。硫普罗宁是一种经典的硫醇抗氧化剂，已被广泛研究用于治疗各种氧化应激相关疾病。
通过蛋白质免疫印迹法和组织学分析，分析OA患者完整和受损软骨中线粒体自噬（PINK1、PARKIN和TOMM20）的表达。进行RNA测序（RNA-seq）分析，以探索硫普罗宁调节软骨细胞线粒体自噬的分子机制，进而找到硫普罗宁的具体靶点。在半月板不稳定（DMM）诱导的OA模型、小鼠原代软骨细胞退变模型和人软骨外植体实验中评估硫普罗宁的治疗效果。通过对线粒体自噬相关蛋白进行小干扰RNA（si-RNA）敲低，进一步研究硫普罗宁的下游分子机制。
软骨中的线粒体自噬水平与OA的严重程度呈负相关。我们发现，硫普罗宁通过增强线粒体自噬促进透明软骨细胞细胞外基质（ECM）的合成代谢，并减轻ROS。此外，硫普罗宁强烈激活线粒体外膜锚定蛋白Bnip3的表达，随后增强Pink1/Parkin信号通路。
这些发现表明，硫普罗宁靶向并激活的Bnip3-Pink1-Parkin信号通路在抑制OA进展中起关键作用。
作为临床上的经典药物，通过本研究为硫普罗宁在OA治疗中开发了一种新的治疗方法。基于硫普罗宁在抑制软骨退变和延缓OA进展方面的显著有效作用，相信硫普罗宁可能成为临床治疗OA的有效候选药物。
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