姜黄素通过抑制 RANK 信号和下游 JNK-BCL2-Beclin1 通路,抑制破骨细胞生成过程中 RANKL 诱导的破骨细胞前体自噬。

IF 4.1 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Dianshan Ke , Haoying Xu , Junyong Han , Hanhao Dai , Xinwen Wang , Jun Luo , Yunlong Yu , Jie Xu
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引用次数: 0

摘要

背景:姜黄素通过抑制破骨细胞生成来改善骨质流失。姜黄素能抑制破骨细胞前体(OCPs)中由 RANKL 促进的自噬,从而起到抗破骨细胞生成的作用。但 RANKL 信号在姜黄素调控的 OCP 自噬中的作用尚不清楚。本研究旨在探讨姜黄素、RANKL信号转导和破骨细胞生成过程中OCP自噬之间的关系:方法:我们研究了姜黄素在OCP中RANKL相关分子信号转导中的作用,并利用流式分选和慢病毒转导技术确定了RANK-TRAF6信号转导在姜黄素处理的破骨细胞生成和OCP自噬中的意义。用Tg-hRANKL小鼠观察姜黄素对RANKL调控的骨丢失、破骨细胞生成和OCP自噬的体内影响。通过挽救实验和BCL2磷酸化检测,探讨了姜黄素与RANKL共同调控OCP自噬过程中JNK-BCL2-Beclin1通路的意义:结果:姜黄素抑制了OCP中与RANKL相关的分子信号转导,抑制了分选的RANK+ OCP的破骨细胞分化和自噬,但对RANK- OCP的破骨细胞分化和自噬没有影响。姜黄素抑制的破骨细胞分化和OCP自噬可通过过表达TRAF6恢复。但在 TRAF6 基因敲除的情况下,姜黄素失去了这些作用。此外,姜黄素还能防止 Tg-hRANKL 小鼠骨量的减少以及 RANK+ OCPs 中小梁破骨细胞形成和自噬的增加。此外,姜黄素与 RANKL 一起抑制的 OCP 自噬可被 JNK 激活剂异霉素和过表达 Beclin1 的 TAT-Beclin1 逆转。姜黄素抑制了OCPs中BCL2在Ser70的磷酸化,并增强了BCL2和Beclin1之间的蛋白相互作用:姜黄素通过抑制RANKL下游的信号通路,抑制了RANKL促进的OCP自噬,从而发挥了抗破骨细胞生成的作用。此外,JNK-BCL2-Beclin1通路在姜黄素调控的OCP自噬过程中发挥了重要作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Curcumin suppresses RANKL-induced osteoclast precursor autophagy in osteoclastogenesis by inhibiting RANK signaling and downstream JNK-BCL2-Beclin1 pathway

Background

Curcumin ameliorates bone loss by inhibiting osteoclastogenesis. Curcumin inhibits RANKL-promoted autophagy in osteoclast precursors (OCPs), which mediates its anti-osteoclastogenic effect. But the role of RANKL signaling in curcumin-regulated OCP autophagy is unknown. This study aimed to explore the relationship between curcumin, RANKL signaling, and OCP autophagy during osteoclastogenesis.

Methods

We investigated the role of curcumin in RANKL-related molecular signaling in OCPs, and identified the significance of RANK-TRAF6 signaling in curcumin-treated osteoclastogenesis and OCP autophagy using flow sorting and lentiviral transduction. Tg-hRANKL mice were used to observe the in vivo effects of curcumin on RANKL-regulated bone loss, osteoclastogenesis, and OCP autophagy. The significance of JNK-BCL2-Beclin1 pathway in curcumin-regulated OCP autophagy with RANKL was explored via rescue assays and BCL2 phosphorylation detection.

Results

Curcumin inhibited RANKL-related molecular signaling in OCPs, and repressed osteoclast differentiation and autophagy in sorted RANK+ OCPs but did not affect those of RANK OCPs. Curcumin-inhibited osteoclast differentiation and OCP autophagy were recovered by TRAF6 overexpression. But curcumin lost these effects under TRAF6 knockdown. Furthermore, curcumin prevented the decrease in bone mass and the increase in trabecular osteoclast formation and autophagy in RANK+ OCPs in Tg-hRANKL mice. Additionally, curcumin-inhibited OCP autophagy with RANKL was reversed by JNK activator anisomycin and TAT-Beclin1 overexpressing Beclin1. Curcumin inhibited BCL2 phosphorylation at Ser70 and enhanced protein interaction between BCL2 and Beclin1 in OCPs.

Conclusions

Curcumin suppresses RANKL-promoted OCP autophagy by inhibiting signaling pathway downstream of RANKL, contributing to its anti-osteoclastogenic effect. Moreover, JNK-BCL2-Beclin1 pathway plays an important role in curcumin-regulated OCP autophagy.

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来源期刊
Biomedical Journal
Biomedical Journal Medicine-General Medicine
CiteScore
11.60
自引率
1.80%
发文量
128
审稿时长
42 days
期刊介绍: Biomedical Journal publishes 6 peer-reviewed issues per year in all fields of clinical and biomedical sciences for an internationally diverse authorship. Unlike most open access journals, which are free to readers but not authors, Biomedical Journal does not charge for subscription, submission, processing or publication of manuscripts, nor for color reproduction of photographs. Clinical studies, accounts of clinical trials, biomarker studies, and characterization of human pathogens are within the scope of the journal, as well as basic studies in model species such as Escherichia coli, Caenorhabditis elegans, Drosophila melanogaster, and Mus musculus revealing the function of molecules, cells, and tissues relevant for human health. However, articles on other species can be published if they contribute to our understanding of basic mechanisms of biology. A highly-cited international editorial board assures timely publication of manuscripts. Reviews on recent progress in biomedical sciences are commissioned by the editors.
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