Department of Orthopedic Surgery, West China Hospital, Sichuan University, Chengdu, China.
Public Laboratory Technology Center, West China Hospital, Sichuan University, Chengdu, China.
J Cell Mol Med. 2024 May;28(10):e18385. doi: 10.1111/jcmm.18385.
Autophagy may play an important role in the occurrence and development of glucocorticoid-induced osteonecrosis of the femoral head (GC-ONFH). Lithium is a classical autophagy regulator, and lithium can also activate osteogenic pathways, making it a highly promising therapeutic agent for GC-ONFH. We aimed to evaluate the potential therapeutic effect of lithium on GC-ONFH. For in vitro experiments, primary osteoblasts of rats were used for investigating the underlying mechanism of lithium's protective effect on GC-induced autophagy levels and osteogenic activity dysfunction. For in vivo experiments, a rat model of GC-ONFH was used for evaluating the therapeutic effect of oral lithium on GC-ONFH and underlying mechanism. Findings demonstrated that GC over-activated the autophagy of osteoblasts and reduced their osteogenic activity. Lithium reduced the over-activated autophagy of GC-treated osteoblasts through PI3K/AKT/mTOR signalling pathway and increased their osteogenic activity. Oral lithium reduced the osteonecrosis rates in a rat model of GC-ONFH, and restrained the increased expression of autophagy related proteins in bone tissues through PI3K/AKT/mTOR signalling pathway. In conclusion, lithium can restrain over-activated autophagy by activating PI3K/AKT/mTOR signalling pathway and up-regulate the expression of genes for bone formation both in GC induced osteoblasts and in a rat model of GC-ONFH. Lithium may be a promising therapeutic agent for GC-ONFH. However, the role of autophagy in the pathogenesis of GC-ONFH remains controversial. Studies are still needed to further explore the role of autophagy in the pathogenesis of GC-ONFH, and the efficacy of lithium in the treatment of GC-ONFH and its underlying mechanisms.
自噬可能在糖皮质激素诱导性股骨头坏死（GC-ONFH）的发生和发展中起重要作用。锂是一种经典的自噬调节剂，锂还可以激活成骨途径，使其成为治疗 GC-ONFH 的极具前景的治疗剂。我们旨在评估锂对 GC-ONFH 的潜在治疗作用。在体外实验中，使用大鼠原代成骨细胞来研究锂对 GC 诱导的自噬水平和成骨活性功能障碍的保护作用的潜在机制。在体内实验中，使用 GC-ONFH 大鼠模型来评估口服锂对 GC-ONFH 的治疗作用及其潜在机制。研究结果表明，GC 过度激活成骨细胞的自噬并降低其成骨活性。锂通过 PI3K/AKT/mTOR 信号通路降低 GC 处理的成骨细胞过度激活的自噬作用，从而增加其成骨活性。口服锂降低了 GC-ONFH 大鼠模型中的骨坏死率，并通过 PI3K/AKT/mTOR 信号通路抑制骨组织中自噬相关蛋白的表达增加。总之，锂通过激活 PI3K/AKT/mTOR 信号通路，抑制过度激活的自噬，并上调 GC 诱导的成骨细胞和成骨细胞中骨形成相关基因的表达，从而减少 GC-ONFH 大鼠模型中的骨坏死率。锂可能是治疗 GC-ONFH 的有前途的治疗剂。然而，自噬在 GC-ONFH 发病机制中的作用仍存在争议。仍需要研究来进一步探索自噬在 GC-ONFH 发病机制中的作用，以及锂在治疗 GC-ONFH 及其潜在机制中的疗效。
