丹参酸A通过含溴结构域蛋白4/Ariadne RBR E3泛素蛋白连接酶1/Rubicon轴促进老年性骨质疏松骨髓间充质干细胞成骨分化

IF 3.3 3区医学 Q1 INTEGRATIVE & COMPLEMENTARY MEDICINE

Journal of Traditional and Complementary Medicine Pub Date : 2025-02-07 DOI:10.1016/j.jtcme.2025.02.003

Zhixian Xu , Jun Luo , Yongfa Zhang , Zhenyu Zhang , Jie Xu

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引用次数: 0

摘要

背景老年性骨质疏松症（SOP）严重困扰着老年人的生活。抑制自噬有助于SOP的进展。同时，丹参酸A （Salvianic acid A， SA）能抑制SOP的进展，调节细胞自噬。然而，SOP中SA与自噬的关系还有待进一步探讨。方法从衰老加速小鼠（SAMP6）中分离骨髓间充质干细胞（BMSCs）。然后用茜素红S （ARS）和碱性磷酸酶（ALP）染色分析骨髓间充质干细胞的成骨情况。同时用Western blot检测蛋白水平。利用Co-IP技术研究了Ariadne RBR E3泛素蛋白连接酶1 （ARIH1）与Rubicon的结合。采用ChIP和双荧光素酶法研究含溴结构域蛋白4 （BRD4）与ARIH1启动子区域的结合。结果SAMP6小鼠骨髓间充质干细胞中BRD4、Rubicon、p62表达上调，ARIH1、Beclin1、ATG5表达下调，LC3II/LC3I比值下调。SA可通过介导骨髓间充质干细胞的自噬作用促进其成骨。此外，SA剂量依赖性上调SAMP6小鼠骨髓间充质干细胞中OPN、OCN和Runx2的水平。ARIH1可通过泛素化降解Rubicon， BRD4可通过转录抑制ARIH1的表达。同时，SA通过介导BRD4/ARIH1/Rubicon轴明显促进BMSCs自噬和成骨。结论sa通过BRD4/ARIH1/Rubicon轴促进老年性骨质疏松骨髓间充质干细胞成骨分化。因此，本研究可为临床制定针对SOP的新策略提供新的理论依据。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Salvianic acid A promotes osteogenic differentiation of bone marrow mesenchymal stem cells in senile osteoporosis through bromodomain-containing protein 4/Ariadne RBR E3 ubiquitin-protein ligase 1/Rubicon axis

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Background

Senile osteoporosis (SOP) seriously disturbs the life of elder people. Inhibition of autophagy can contribute to the progression of SOP. Meanwhile, Salvianic acid A (SA) could inhibit the progression of SOP, and it could regulate the autophagy. However, the relationship between SA and autophagy in SOP remains to be further explored.

Methods

Bone marrow mesenchymal stem cells (BMSCs) were isolated from senescence-accelerated mouse propensity 6 (SAMP6) mice. Then, Alizarin red S (ARS) and alkaline phosphatase (ALP) staining were performed to analyze the osteogenesis in BMSCs. Meanwhile, protein levels were investigated using Western blot. The binding between Ariadne RBR E3 ubiquitin-protein ligase 1 (ARIH1) and Rubicon was investigated using Co-IP. ChIP and Dual-luciferase assay were used to explore the binding between bromodomain-containing protein 4 (BRD4) and ARIH1 promoter region.

Results

The levels of BRD4, Rubicon and p62 were upregulated in BMSCs from SAMP6 mice, while ARIH1, Beclin1, ATG5 and the ratio of LC3II/LC3I were downregulated. SA could promote the osteogenesis of BMSCs through mediating the autophagy. In addition, SA dose-dependently upregulated the levels of OPN, OCN and Runx2 in BMSCs from SAMP6 mice. ARIH1 could degrade Rubicon through ubiquitination, and BRD4 could transcriptionally inhibit the expression of ARIH1. Meanwhile, SA obviously promoted the autophagy and osteogenesis in BMSCs through mediation of BRD4/ARIH1/Rubicon axis.

Conclusion

SA promoted osteogenic differentiation of BMSCs in senile osteoporosis through BRD4/ARIH1/Rubicon axis. Thus, our study might provide a new theoretical basis for developing the new strategies against SOP in clinic.

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来源期刊

Journal of Traditional and Complementary Medicine Medicine-Complementary and Alternative Medicine

CiteScore

9.30

自引率

6.70%

发文量

审稿时长

66 days

期刊介绍： eJTCM is committed to publish research providing the biological and clinical grounds for using Traditional and Complementary Medical treatments as well as studies that demonstrate the pathophysiological and molecular/biochemical bases supporting the effectiveness of such treatments. Review articles are by invitation only. eJTCM is receiving an increasing amount of submission, and we need to adopt more stringent criteria to select the articles that can be considered for peer review. Note that eJTCM is striving to increase the quality and medical relevance of the publications.