Intervertebral disc degeneration (IVDD) is a chronic condition that significantly affects the quality of life, particularly among the aging population. This degenerative disease is characterized by the aging and loss of proliferative capacity in nucleus pulposus cells (NPCs), processes intricately linked to mitochondrial dynamics and autophagic flux. Recent research conducted by Yuxin Jin, Ouqiang Wu, Qizhu Chen, Linjie Chen, Zhiguang Zhang, Haijun Tian, Hao Zhou, Kai Zhang, Jianyuan Gao, Xinzhou Wang, Zhenyu Guo, Jing Sun, Kenny Yat Hong Kwan, Morgan Jones, Yan Michael Li, Ehsan Nazarzadeh Zare, Pooyan Makvandi, Xiangyang Wang, Shuying Shen, and Aimin Wu sheds light on the mechanisms underlying NPC degeneration and presents a potential therapeutic avenue.
The study reveals that the absence of BCL2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3) correlates with senescence-related degeneration of NPCs, leading to disrupted mitochondrial quality control. This finding emphasizes the critical role of BNIP3 in maintaining the health and function of NPCs, as it is essential for mitochondrial dynamics.
Bone marrow mesenchymal stem cells (BMSCs) have garnered attention for their multidirectional differentiation potential and their ability to produce extracellular vesicles (EVs) containing various cellular activators. In this study, the researchers induced BMSCs under hypoxic conditions to enhance the delivery of BNIP3-rich extracellular vesicles to NPCs. This innovative approach aimed to mitigate aging-associated mitochondrial autophagic flux, thereby promoting the clearance of damaged mitochondria and restoring mitochondrial quality control in NPCs.
At the mechanistic level, the study highlights a novel interaction between BNIP3 and the membrane-bound protein annexin A2 (ANXA2). This interaction facilitates the release of the transcription factor EB (TFEB) from the ANXA2-TFEB complex, enabling TFEB’s nuclear translocation. Once in the nucleus, TFEB regulates autophagy and lysosomal gene activation, further supporting mitochondrial health and function.
To validate the in vivo efficacy of this therapeutic strategy, the researchers established a rat model of IVDD. The results demonstrated that the administration of BNIP3-rich exosomes significantly repaired disc injuries, delayed NPC aging, and promoted extracellular matrix (ECM) synthesis. This research presents a promising breakthrough in the treatment of IVDD, indicating that hypoxia-induced BMSC exosomes can deliver BNIP3-rich vesicles to alleviate disc degeneration via activation of the mitochondrial BNIP3/ANXA2/TFEB axis.
In conclusion, the study opens new avenues for IVDD treatment by targeting mitochondrial dynamics and autophagic processes. The findings underscore the potential of using BMSC-derived extracellular vesicles as a therapeutic strategy to combat intervertebral disc degeneration, offering hope for improved outcomes for those affected by this debilitating condition. The research conducted by this collaborative group serves as a significant step towards understanding and addressing the complexities of IVDD, paving the way for future therapeutic developments.