Activating transcription factor 4 (ATF4) is critical for chondrocyte proliferation and bone formation. Exosomes are considered as promising gene‐delivery vehicles for the treatment of osteoarthritis (OA). This study utilized the serum‐derived exosomes from OA mice as the gene‐delivery vehicles for ATF4 gene therapy and explored their therapeutic effects on OA. Meniscus injury‐induced OA model was established by the excision of anterior part of medial meniscus in the right knee of C57BL/6J mice. Exosomes were isolated from serum samples of sham and OA mice, and were referred to as sham‐Exo and OA‐Exo, respectively. ATF4‐overexpressing OA‐Exo (ATF4‐OA‐Exo) was developed by introducing ATF4 mRNA into OA‐Exo via electroporation. Four weeks after surgery, OA mice received intra‐articular injections of sham‐Exo, OA‐Exo, and ATF4‐OA‐Exo, respectively. The results showed that intra‐articular injection of ATF4‐OA‐Exo alleviated articular cartilage degeneration or damage and inflammatory response of OA mice. Autophagy was weakened in knee joint cartilage of OA mice, which was partially restored by intra‐articular injection of ATF4‐OA‐Exo. Further in vitro assays revealed that ATF4‐OA‐Exo promoted chondrocyte autophagy and inhibited chondrocyte apoptosis in the TNF‐α‐ or tunicamycin‐treated chondrocytes. Together, ATF4‐modified serum exosomes derived from OA mice protect cartilage and alleviate OA progression by inducing autophagy.

中文翻译：

---

来自骨关节炎小鼠的 ATF4 修饰的血清外泌体通过诱导自噬抑制骨关节炎

激活转录因子 4 (ATF4) 对软骨细胞增殖和骨形成至关重要。外泌体被认为是治疗骨关节炎（OA）的有前途的基因传递载体。本研究利用来自 OA 小鼠的血清来源的外泌体作为 ATF4 基因治疗的基因载体，并探讨了它们对 OA 的治疗作用。通过切除C57BL/6J小鼠右膝内侧半月板前部建立半月板损伤致OA模型。外泌体是从假小鼠和 OA 小鼠的血清样本中分离出来的，分别称为 sham-Exo 和 OA-Exo。ATF4 过表达 OA-Exo (ATF4-OA-Exo) 是通过电穿孔将 ATF4 mRNA 引入 OA-Exo 开发的。手术后 4 周，OA 小鼠分别接受了 sham-Exo、OA-Exo 和 ATF4-OA-Exo 的关节内注射。结果表明，关节内注射 ATF4-OA-Exo 可减轻 OA 小鼠的关节软骨退化或损伤和炎症反应。OA小鼠膝关节软骨自噬减弱，通过关节内注射ATF4-OA-Exo部分恢复。进一步的体外试验表明，在 TNF-α 或衣霉素处理的软骨细胞中，ATF4-OA-Exo 促进软骨细胞自噬并抑制软骨细胞凋亡。总之，来自 OA 小鼠的 ATF4 修饰的血清外泌体通过诱导自噬来保护软骨并缓解 OA 进展。通过关节内注射 ATF4-OA-Exo 部分恢复。进一步的体外试验表明，在 TNF-α 或衣霉素处理的软骨细胞中，ATF4-OA-Exo 促进软骨细胞自噬并抑制软骨细胞凋亡。总之，来自 OA 小鼠的 ATF4 修饰的血清外泌体通过诱导自噬来保护软骨并缓解 OA 进展。通过关节内注射 ATF4-OA-Exo 部分恢复。进一步的体外试验表明，在 TNF-α 或衣霉素处理的软骨细胞中，ATF4-OA-Exo 促进软骨细胞自噬并抑制软骨细胞凋亡。总之，来自 OA 小鼠的 ATF4 修饰的血清外泌体通过诱导自噬来保护软骨并缓解 OA 进展。