Department of Orthopedics, The First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, 215006, China.
Department of Orthopedics, Taizhou People's Hospital, Taizhou, 225300, China.
Stem Cell Res Ther. 2023 Jul 3;14(1):171. doi: 10.1186/s13287-023-03371-y.
Ferroptosis is an iron-related form of programmed cell death. Accumulating evidence has identified the pathogenic role of ferroptosis in multiple orthopedic disorders. However, the relationship between ferroptosis and SONFH is still unclear. In addition, despite being a common disease in orthopedics, there is still no effective treatment for SONFH. Therefore, clarifying the pathogenic mechanism of SONFH and investigating pharmacologic inhibitors from approved clinical drugs for SONFH is an effective strategy for clinical translation. Melatonin (MT), an endocrine hormone that has become a popular dietary supplement because of its excellent antioxidation, was supplemented from an external source to treat glucocorticoid-induced damage in this study.
Methylprednisolone, a commonly used glucocorticoid in the clinic, was selected to simulate glucocorticoid-induced injury in the current study. Ferroptosis was observed through the detection of ferroptosis-associated genes, lipid peroxidation and mitochondrial function. Bioinformatics analysis was performed to explore the mechanism of SONFH. In addition, a melatonin receptor antagonist and shGDF15 were applied to block the therapeutic effect of MT to further confirm the mechanism. Finally, cell experiments and the SONFH rat model were used to detect the therapeutic effects of MT.
MT alleviated bone loss in SONFH rats by maintaining BMSC activity through suppression of ferroptosis. The results are further verified by the melatonin MT2 receptor antagonist that can block the therapeutic effects of MT. In addition, bioinformatic analysis and subsequent experiments confirmed that growth differentiation factor 15 (GDF15), a stress response cytokine, was downregulated in the process of SONFH. On the contrary, MT treatment increased the expression of GDF15 in bone marrow mesenchymal stem cells. Lastly, rescue experiments performed with shGDF15 confirmed that GDF15 plays a key role in the therapeutic effects of melatonin.
We proposed that MT attenuated SONFH by inhibiting ferroptosis through the regulation of GDF15, and supplementation with exogenous MT might be a promising method for the treatment of SONFH.
铁死亡是一种与铁相关的程序性细胞死亡形式。越来越多的证据表明铁死亡在多种骨科疾病中起致病作用。然而，铁死亡与 SONFH 的关系尚不清楚。此外，尽管 SONFH 是骨科的常见病，但目前仍没有有效的治疗方法。因此，阐明 SONFH 的发病机制，并从已批准的临床药物中寻找 SONFH 的药物抑制剂是一种有效的临床转化策略。褪黑素（MT）是一种内分泌激素，由于其出色的抗氧化作用，已成为一种流行的膳食补充剂，本研究从外部补充 MT 以治疗糖皮质激素诱导的损伤。
选择临床上常用的糖皮质激素甲泼尼龙来模拟本研究中的糖皮质激素诱导损伤。通过检测铁死亡相关基因、脂质过氧化和线粒体功能来观察铁死亡。进行生物信息学分析以探讨 SONFH 的发病机制。此外，应用褪黑素受体拮抗剂和 shGDF15 来阻断 MT 的治疗作用，以进一步证实机制。最后，通过细胞实验和 SONFH 大鼠模型来检测 MT 的治疗效果。
MT 通过抑制铁死亡来维持 BMSC 活性，从而减轻 SONFH 大鼠的骨质流失。褪黑素 MT2 受体拮抗剂可以阻断 MT 的治疗作用，进一步验证了这一结果。此外，生物信息学分析和后续实验证实，生长分化因子 15（GDF15），一种应激反应细胞因子，在 SONFH 过程中下调。相反，MT 处理增加了骨髓间充质干细胞中 GDF15 的表达。最后，用 shGDF15 进行的挽救实验证实 GDF15 在 MT 的治疗作用中起关键作用。
我们提出 MT 通过调节 GDF15 抑制铁死亡来减轻 SONFH，补充外源性 MT 可能是治疗 SONFH 的一种有前途的方法。
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