Magnesium-based implants accelerate femoral fracture healing through promoting histone lactylation-mediated osteoclastogenesis inhibition

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences Pub Date : 2025-04-17 DOI:10.1016/j.lfs.2025.123639

Junyi Shen , Yilun Pei , Shangying Bai , Simeng Lei , Suhang Xia , Jie Zhang , Xingyu Li , Hanchi Xu , Xinyu Zheng , Xuezhen Shen , Huanjun Zhao , Liang Liu , Xinlin Yang , Xuefei Wang

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引用次数: 0

Abstract

Aims

To investigate the molecular mechanisms by which magnesium (Mg)-based implants, specifically Mg-containing intramedullary nails (Mg-IMNs), promote femoral fracture healing.

Materials and methods

Rats with femoral fractures were treated with Mg-IMNs. In vitro experiments were conducted to assess the impact of Mg²⁺ on osteoclastogenesis and histone lactylation. Histological analysis, Western blotting, and qRT-PCR were employed to evaluate osteoclast maturation and the molecular pathways involved. In vivo, lactate was administered to replicate Mg-IMN effects, and lactate production was inhibited to observe potential reversal effects.

Key findings

Mg-IMNs significantly enhanced fracture healing by inhibiting osteoclastogenesis. Mg²⁺ promoted intracellular lactate production, leading to histone lactylation, which suppressed osteoclast maturation by downregulating NFATc1. The P300/H3K18LA/HDAC1 pathway was identified as a key mediator in this process. Additionally, lactate administration mimicked the effects of Mg-IMNs, while blocking lactate reversed these effects.

Significance

This study uncovers a novel mechanism by which Mg²⁺ promotes fracture healing through histone lactylation-mediated inhibition of osteoclastogenesis. These findings offer new therapeutic strategies for enhancing fracture repair via epigenetic regulation.

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镁基植入物通过促进组蛋白乳酸化介导的破骨细胞发生抑制来加速股骨骨折愈合

目的探讨镁基植入物，特别是含镁髓内钉（Mg- imns）促进股骨骨折愈合的分子机制。材料与方法采用Mg-IMNs治疗股骨骨折大鼠。体外实验评估Mg2+对破骨细胞生成和组蛋白乳酸化的影响。采用组织学分析、Western blotting和qRT-PCR评价破骨细胞成熟及其分子通路。在体内，给药乳酸以复制Mg-IMN效应，并抑制乳酸的产生以观察潜在的逆转效应。主要发现smg - imns通过抑制破骨细胞生成显著促进骨折愈合。Mg2+促进细胞内乳酸生成，导致组蛋白乳酸化，通过下调NFATc1抑制破骨细胞成熟。P300/H3K18LA/HDAC1通路被确定为这一过程的关键中介。此外，乳酸管理模拟Mg-IMNs的作用，而阻断乳酸逆转这些作用。本研究揭示了Mg2+通过组蛋白乳酸化介导的破骨细胞生成抑制促进骨折愈合的新机制。这些发现为通过表观遗传调控加强骨折修复提供了新的治疗策略。

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

Life sciences 医学-药学

CiteScore

12.20

自引率

1.60%

发文量

841

审稿时长

6 months

期刊介绍： Life Sciences is an international journal publishing articles that emphasize the molecular, cellular, and functional basis of therapy. The journal emphasizes the understanding of mechanism that is relevant to all aspects of human disease and translation to patients. All articles are rigorously reviewed. The Journal favors publication of full-length papers where modern scientific technologies are used to explain molecular, cellular and physiological mechanisms. Articles that merely report observations are rarely accepted. Recommendations from the Declaration of Helsinki or NIH guidelines for care and use of laboratory animals must be adhered to. Articles should be written at a level accessible to readers who are non-specialists in the topic of the article themselves, but who are interested in the research. The Journal welcomes reviews on topics of wide interest to investigators in the life sciences. We particularly encourage submission of brief, focused reviews containing high-quality artwork and require the use of mechanistic summary diagrams.