Zoledronic acid relieves steroid-induced avascular necrosis of femoral head via inhibiting FOXD3 mediated ANXA2 transcriptional activation

IF 3.5 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Bone Pub Date : 2024-08-03 DOI:10.1016/j.bone.2024.117222

Yu Lin , Min Chen , Wenbin Guo , Shengliang Qiu , Lihui Chen , Wenge Liu

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引用次数: 0

Abstract

Background

Zoledronic acid (ZOL) is a type of bisphosphonate with good therapeutic effects on orthopaedic diseases. However, the pharmacological functions of ZOL on steroid-induced avascular necrosis of femoral head (SANFH) and the underlying mechanism remain unclear, which deserve further research.

Methods

SANFH models both in vivo and in vitro were established by dexamethasone (Dex) stimulation. Osteoclastogenesis was examined by TRAP staining. Immunofluorescence was employed to examine autophagy marker (LC3) level. Cell apoptosis was analyzed by TUNEL staining. The interaction between Foxhead box D3 protein (FOXD3) and Annexin A2 (ANXA2) promoter was analyzed using ChIP and dual luciferase reporter gene assays.

Results

Dex aggravated osteoclastogenesis and induced osteoclast differentiation and autophagy in vitro, which was abrogated by ZOL treatment. PI3K inhibitor LY294002 abolished the inhibitory effect of ZOL on Dex-induced osteoclast differentiation and autophagy. FOXD3 overexpression neutralized the downregulation effects of ZOL on Dex-induced osteoclasts by transcriptionally activating ANXA2. ANXA2 knockdown reversed the effect of FOXD3 overexpression on ZOL-mediated biological effects in Dex-treated osteoclasts. In addition, ZOL improved SANFH symptoms in rats.

Conclusion

ZOL alleviated SANFH through regulating FOXD3 mediated ANXA2 transcriptional activity and then promoting PI3K/AKT/mTOR pathway, revealing that FOXD3 might be a target for ZOL in SANFH treatment.

查看原文本刊更多论文

唑来膦酸通过抑制 FOXD3 介导的 ANXA2 转录激活，缓解类固醇诱导的股骨头血管性坏死。

背景：唑来膦酸（ZOL）是一种双膦酸盐，对骨科疾病具有良好的治疗效果。然而，唑来膦酸对类固醇诱导的股骨头血管性坏死（SANFH）的药理作用及其内在机制仍不清楚，值得进一步研究：方法：通过地塞米松（Dex）刺激建立体内和体外股骨头坏死模型。方法：通过地塞米松（Dex）刺激建立体内和体外的 SANFH 模型。免疫荧光法检测自噬标记物（LC3）水平。通过TUNEL染色分析细胞凋亡。利用ChIP和双荧光素酶报告基因实验分析了Foxhead box D3蛋白（FOXD3）和Annexin A2（ANXA2）启动子之间的相互作用：结果：Dex可加重破骨细胞的生成，并诱导体外破骨细胞分化和自噬，ZOL处理可减轻这种作用。PI3K抑制剂LY294002可消除ZOL对Dex诱导的破骨细胞分化和自噬的抑制作用。FOXD3的过表达通过转录激活ANXA2中和了ZOL对Dex诱导的破骨细胞的下调作用。ANXA2 敲除逆转了 FOXD3 过表达对 ZOL 介导的 Dex 治疗破骨细胞生物效应的影响。此外，ZOL还能改善大鼠的SANFH症状：结论：ZOL通过调节FOXD3介导的ANXA2转录活性，进而促进PI3K/AKT/mTOR通路，缓解了SANFH，揭示了FOXD3可能是ZOL治疗SANFH的靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Bone 医学-内分泌学与代谢

CiteScore

8.90

自引率

4.90%

发文量

264

审稿时长

30 days

期刊介绍： BONE is an interdisciplinary forum for the rapid publication of original articles and reviews on basic, translational, and clinical aspects of bone and mineral metabolism. The Journal also encourages submissions related to interactions of bone with other organ systems, including cartilage, endocrine, muscle, fat, neural, vascular, gastrointestinal, hematopoietic, and immune systems. Particular attention is placed on the application of experimental studies to clinical practice.