敲除Gfi1可增加BMSCs外泌miR-150-3p,从而通过BTRC/Nrf2轴抑制类固醇诱导的股骨头坏死中的成骨细胞铁凋亡

IF 1.3 4区 医学 Q4 ENDOCRINOLOGY & METABOLISM Endocrine journal Pub Date : 2025-02-03 Epub Date: 2024-12-14 DOI:10.1507/endocrj.EJ24-0306
Liwen Zheng, Changjie Zhang, Lele Liao, Zhijie Hai, Xin Luo, Haoliang Xiao
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引用次数: 0

摘要

成骨细胞的铁下垂已被证明在类固醇诱导的股骨头骨坏死(SONFH)的发展中起重要作用。此外,microrna (mirna)已被确定为SONFH进展的调节因子。然而,mirna在成骨细胞铁下垂调控中的确切作用尚不清楚。本研究探讨了来自骨髓间充质干细胞(BMSCs)的外泌体miR-150-3p在SONFH成骨细胞铁凋亡中的作用。采用地塞米松(DEX)治疗成骨细胞诱导铁下垂。将不同水平miR-150-3p的骨髓间充质干细胞外泌体与细胞共培养。为了验证生长因子独立1 (Gfi1)与miR-150-3p启动子之间的靶向关系,以及miR-150-3p与含有E3泛素蛋白连接酶(BTRC)的β -转导重复序列之间的靶向关系,分别采用染色质免疫沉淀(ChIP), RNA免疫沉淀(RIP)和双荧光素酶测定。发现BMSCs-Exos-miR-150-3p减轻了dex引发的成骨细胞铁下垂。MiR-150-3p直接靶向BTRC,导致其在成骨细胞中下调。BTRC/Nuclear factor erythroid 2-related factor 2 (Nrf2)通路参与BMSCs-Exos-miR-150-3p抑制dex诱导的成骨细胞铁凋亡。BTRC的过表达逆转了BMSCs-Exos-miR-150-3p的抑制作用。在SONFH大鼠模型中,BMSCs-Exos-miR-150-3p通过BTRC/Nrf2减轻成骨细胞的铁下沉。此外,Gfi1结合到miR-150-3p启动子并抑制其转录。Gfi1沉默可提高miR-150-3p水平,提高骨髓间充质干细胞的细胞活力。总之,我们的研究结果表明,BMSCs-Exos-miR-150-3p通过调节BTRC/Nrf2抑制铁下垂来缓解SONFH, miR-150-3p可能是SONFH治疗的潜在靶点。
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Knockdown of Gfi1 increases BMSCs exosomal miR-150-3p to inhibit osteoblast ferroptosis in steroid-induced osteonecrosis of the femoral head through BTRC/Nrf2 axis.

The ferroptosis of osteoblasts has been demonstrated to play a significant role in the development of steroid-induced osteonecrosis of the femoral head (SONFH). Additionally, microRNAs (miRNAs) have been identified as regulators of SONFH progression. However, the precise role of miRNAs in the regulation of osteoblast ferroptosis remains unclear. This study explored the role of exosomal miR-150-3p, derived from bone marrow mesenchymal stem cells (BMSCs), in osteoblast ferroptosis in SONFH. Dexamethasone (DEX) was used to treat osteoblasts to induce ferroptosis. BMSCs exosomes with different levels of miR-150-3p were introduced into a co-culture with the cells. To verify the targeting relationship between growth factor independence 1 (Gfi1) and the miR-150-3p promoter, as well as between miR-150-3p and beta-transducin repeat containing E3 ubiquitin protein ligase (BTRC), respectively, chromatin immunoprecipitation (ChIP), RNA immunoprecipitation (RIP), and dual luciferase assays were employed. It was found that BMSCs-Exos-miR-150-3p mitigated DEX-triggered ferroptosis in osteoblasts. MiR-150-3p directly targeted BTRC, leading to its downregulation in osteoblasts. The BTRC/Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway was involved in the inhibition of DEX-induced osteoblast ferroptosis by BMSCs-Exos-miR-150-3p. Overexpression of BTRC reversed the inhibitory effect of BMSCs-Exos-miR-150-3p. In a SONFH rat model, BMSCs-Exos-miR-150-3p alleviated ferroptosis in osteoblasts through BTRC/Nrf2. In addition, Gfi1 bonded to the miR-150-3p promoter and inhibited its transcription. Gfi1 silencing elevated miR-150-3p levels and improves cell viability of BMSCs. In conclusion, our results suggest that BMSCs-Exos-miR-150-3p alleviates SONFH by suppressing ferroptosis through the regulation of BTRC/Nrf2 and miR-150-3p may be a potential target for SONFH treatment.

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来源期刊
Endocrine journal
Endocrine journal 医学-内分泌学与代谢
CiteScore
4.30
自引率
5.00%
发文量
224
审稿时长
1.5 months
期刊介绍: Endocrine Journal is an open access, peer-reviewed online journal with a long history. This journal publishes peer-reviewed research articles in multifaceted fields of basic, translational and clinical endocrinology. Endocrine Journal provides a chance to exchange your ideas, concepts and scientific observations in any area of recent endocrinology. Manuscripts may be submitted as Original Articles, Notes, Rapid Communications or Review Articles. We have a rapid reviewing and editorial decision system and pay a special attention to our quick, truly scientific and frequently-citable publication. Please go through the link for author guideline.
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