ESC-sEVs调控软骨代谢稳态防治退行性骨关节炎的机制研究

骨关节炎（Osteoarthritis，OA）是目前尚缺乏理想治疗手段的衰老相关疾病，亟待我们去探索干预其发生发展的新思路和新技术。OA的发生发展与代谢稳态失衡密切相关，其中软骨细胞衰老是影响代谢稳态的重要因素，缓解软骨细胞衰老维持软骨代谢稳态可能防治OA。研究表明FOXOs在调控关节软骨代谢稳态中占重要地位，其是否通过调控软骨细胞衰老而维持软骨代谢稳态尚不清楚。我们的前期研究发现OA模型中软骨细胞的衰老与FOXOs调控有关，胚胎干细胞来源的细胞外囊泡（ESC-sEVs）可影响FOXOs的表达，改善软骨细胞衰老，促进关节软骨的修复。本研究拟进一步开展系列实验，明确关键FOXOs通过调控软骨衰老维持代谢稳态的功能及具体分子机制；筛选并验证ESC-sEVs可能运载的特异转录因子通过调控关键FOXOs而改善软骨细胞衰老维持软骨代谢稳态的作用及具体机制。为防治老年性OA提供新的思路与技术策略。

Osteoarthritis is an aging-related disease that currently lacks satisfactory treatments. It is urgent for us to explore new strategies and techniques to intervene in its development. The occurrence and development of osteoarthritis is closely associated with the imbalance of cartilage metabolic homeostasis. Improving chondrocytes senescence can maintain cartilage metabolic homeostasis and prevent osteoarthritis. Recent studies have demonstrated that FOXOs play an important role in regulating cartilage metabolic homeostasis. However, whether the protective effect of FOXOs are associated with the regulation of chondrocyte senescence is still unknown. In our preliminary study, we found that FOXOs are involved in the regulation of chondrocytes senescence in mouse osteoarthritis models. Extracellular vesicles derived from embryonic stem cells (ESC-sEVs) can affect FOXOs expression, significantly reduce chondrocyte senescent levels, and promote the repair of articular cartilage. Hereby, this study intends to further disclose the specific mechanism of key FOXOs in the maintenance of chondrocyte senescence; to verify the specific protein molecule of ESC-sEVs regulating key FOXOs, and to illuminate the molecular mechanism of ESC-sEVs regulating cartilage metabolic homeostasis. Our purpose is to provide new insights and strategies for the prevention and the treatment of osteoarthritis.