Department of Orthopaedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Lujiang Road No. 17, Hefei, 230001 Anhui, China.
Department of Oncology, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Lujiang Road No. 17, Hefei, 230001 Anhui, China.
Oxid Med Cell Longev. 2022 Aug 18;2022:8223737. doi: 10.1155/2022/8223737. eCollection 2022.
Steroid-induced osteoporosis (SIOP) is a form of secondary osteoporosis, but its specific mechanism remains unclear. Glucocorticoid (GC-)-induced death of osteoblasts and bone marrow mesenchymal stem cells (BMSCs) is an important factor in SIOP. Ferroptosis is an iron-dependent type of programmed cell death and can be induced by many factors. Herein, we aimed to explore whether GCs cause ferroptosis of BMSCs, identify pathways as possible therapeutic targets, and determine the underlying mechanisms of action. In this study, we used high-dose dexamethasone (DEX) to observe whether GCs induce ferroptosis of BMSCs. Additionally, we established a rat SIOP model and then assessed whether melatonin (MT) could inhibit the ferroptosis pathway to provide early protection against GC-induced SIOP and investigated the signaling pathways involved. experiments confirmed that DEX induces ferroptosis in BMSCs. MT significantly alleviates GC-induced ferroptosis of BMSCs. Pathway analysis showed that MT ameliorates ferroptosis by activating the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) axis. MT upregulates the expression of PI3K, which is an important regulator of ferroptosis resistance. PI3K activators mimic the antiferroptotic effect of MT, but when the PI3K pathway is blocked, the effect of MT is weakened. Using experiments, we confirmed the in vitro results and observed that MT can obviously protect against SIOP induced by GC. Notably, even after the initiation of GC-induced ferroptosis, MT can confer protection against SIOP. Our research confirms that GC-induced ferroptosis is closely related to SIOP. MT can inhibit ferroptosis by activating the PI3K/AKT/mTOR signaling pathway, thereby inhibiting the occurrence of SIOP. Therefore, MT may be a novel agent for preventing and treating SIOP.
激素诱导性骨质疏松症（SIOP）是一种继发性骨质疏松症，但具体机制尚不清楚。糖皮质激素（GC）诱导成骨细胞和骨髓间充质干细胞（BMSCs）死亡是 SIOP 的一个重要因素。铁死亡是一种铁依赖性的程序性细胞死亡方式，可由多种因素诱导。在此，我们旨在探讨 GC 是否导致 BMSCs 发生铁死亡，确定可能的治疗靶点途径，并确定其作用机制。在本研究中，我们使用高剂量地塞米松（DEX）观察 GC 是否诱导 BMSCs 发生铁死亡。此外，我们建立了大鼠 SIOP 模型，然后评估褪黑素（MT）是否可以抑制铁死亡途径，为 GC 诱导的 SIOP 提供早期保护，并探讨涉及的信号通路。实验证实 DEX 诱导 BMSCs 发生铁死亡。MT 显著减轻 GC 诱导的 BMSCs 铁死亡。通路分析表明，MT 通过激活磷脂酰肌醇 3-激酶（PI3K）/蛋白激酶 B（AKT）/雷帕霉素靶蛋白（mTOR）轴来改善铁死亡。MT 上调 PI3K 的表达，PI3K 是铁死亡抵抗的重要调节因子。PI3K 激活剂模拟 MT 的抗铁死亡作用，但当 PI3K 通路被阻断时，MT 的作用减弱。通过实验，我们证实了体外结果，并观察到 MT 可以明显保护 GC 诱导的 SIOP。值得注意的是，即使在 GC 诱导的铁死亡发生后，MT 也可以对 SIOP 提供保护。我们的研究证实，GC 诱导的铁死亡与 SIOP 密切相关。MT 通过激活 PI3K/AKT/mTOR 信号通路抑制铁死亡，从而抑制 SIOP 的发生。因此，MT 可能是预防和治疗 SIOP 的一种新型药物。
