阿托伐他汀通过调节 Wnt5a 的释放对类固醇诱发的股骨头坏死有预防作用。

IF 4.8 2区 医学 Q1 TOXICOLOGY Archives of Toxicology Pub Date : 2024-07-07 DOI:10.1007/s00204-024-03817-z
Junfeng Wu, Tao Chen, Minghang Zhang, Xing Li, Rongkun Fu, Jianzhong Xu, Andreas Nüssler, Chenxi Gu
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引用次数: 0

摘要

类固醇诱发的股骨头坏死(SONFH)是年轻人骨坏死的一种常见形式。必须采用更有效的临床策略来预防和治疗这种疾病。SONFH的发病机制之一是由于长期大量使用糖皮质激素(GCs)导致骨髓脂肪细胞和成骨细胞的正常分化被破坏。体外观察发现,阿托伐他汀(ATO)能有效抑制地塞米松(DEX)对骨髓间充质干细胞(BMSCs)的影响,特别是通过增强其脂肪生成分化而阻碍其骨生成分化。为了进一步研究其潜在机制,我们对接受不同处理的骨髓间充质干细胞进行了转录组测序,结果发现Wnt5a是受ATO调控的一个关键基因。分析表明,ATO 在通过 WNT5A/LRP5 通路调节 Wnt 标准信号通路的同时,还能增强 Wnt5a 的表达并调节 MAPK 通路。我们的实验结果进一步证明,ATO和DEX联合治疗可有效减轻DEX的影响,导致成骨基因(Runx2、Alpl、Tnfrsf11b、Ctnnb1、Col1a)上调,成脂基因(Pparg、Cebpb、Lpl)下调,同时导致Wnt5a表达上调。因此,这项研究为了解利用 ATO 预防 SONFH 的潜在机制提供了有价值的见解,从而对临床预防和治疗 SONFH 具有重要意义。
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Atorvastatin exerts a preventive effect against steroid-induced necrosis of the femoral head by modulating Wnt5a release

Steroid-induced osteonecrosis of the femoral head (SONFH) is a prevalent form of osteonecrosis in young individuals. More efficacious clinical strategies must be used to prevent and treat this condition. One of the mechanisms through which SONFH operates is the disruption of normal differentiation in bone marrow adipocytes and osteoblasts due to prolonged and extensive use of glucocorticoids (GCs). In vitro, it was observed that atorvastatin (ATO) effectively suppressed the impact of dexamethasone (DEX) on bone marrow mesenchymal stem cells (BMSCs), specifically by augmenting their lipogenic differentiation while impeding their osteogenic differentiation. To investigate the underlying mechanisms further, we conducted transcriptome sequencing of BMSCs subjected to different treatments, leading to the identification of Wnt5a as a crucial gene regulated by ATO. The analyses showed that ATO exhibited the ability to enhance the expression of Wnt5a and modulate the MAPK pathway while regulating the Wnt canonical signaling pathway via the WNT5A/LRP5 pathway. Our experimental findings provide further evidence that the combined treatment of ATO and DEX effectively mitigates the effects of DEX, resulting in the upregulation of osteogenic genes (Runx2, Alpl, Tnfrsf11b, Ctnnb1, Col1a) and the downregulation of adipogenic genes (Pparg, Cebpb, Lpl), meanwhile leading to the upregulation of Wnt5a expression. So, this study offers valuable insights into the potential mechanism by which ATO can be utilized in the prevention of SONFH, thereby holding significant implications for the prevention and treatment of SONFH in clinical settings.

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来源期刊
Archives of Toxicology
Archives of Toxicology 医学-毒理学
CiteScore
11.60
自引率
4.90%
发文量
218
审稿时长
1.5 months
期刊介绍: Archives of Toxicology provides up-to-date information on the latest advances in toxicology. The journal places particular emphasis on studies relating to defined effects of chemicals and mechanisms of toxicity, including toxic activities at the molecular level, in humans and experimental animals. Coverage includes new insights into analysis and toxicokinetics and into forensic toxicology. Review articles of general interest to toxicologists are an additional important feature of the journal.
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