Macrophage migration inhibitory factor promotes heterotopic ossification by mediating ROS/HIF-1α positive feedback loop and activating Wnt/β-catenin signaling pathway

IF 3.5 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Bone Pub Date : 2024-11-15 DOI:10.1016/j.bone.2024.117331

Ping Li , Wensheng Zhang , Jie Zhang , Jie Liu , Jiaming Fu , Zhengnong Wei , Shiyong Le , Jiajia Xu , Liang Wang , Zhongmin Zhang

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Abstract

Background

Heterotopic ossification (HO) refers to the development of bone tissue in areas other than the skeletal system. The development and maturation of the skeletal system are significantly influenced by macrophage migration inhibitory factor (MIF). The objective of this study was to examine the impact of MIF on the in vitro osteogenic differentiation and mineralization of tendon-derived stem cells (TDSCs), mediated by a positive feedback loop involving ROS/HIF-1α/MIF.

Methods

TDSCs were isolated and identified from the hind limbs of C57/BL6 mice. The functional and procedural roles of MIF in HO, focusing on the impact of MIF on the differentiation of TDSCs into bone-forming cells were investigated in vitro. Seventy-five mice were randomly assigned to five groups. Gene expression and histological analyses of MIF and its receptors, and determine the expression of osteogenic markers in vivo.

Results

The results revealed a positive and concentration-dependent effect of MIF on the osteogenic differentiation of TDSCs. Furthermore, an ROS/HIF-1α/MIF positive loop was detected in the simulated early trauma hypoxic microenvironment, resulting in a 3 to 4 folds increase in MIF expression levels. MIF was also found to enhance double the expression levels of markers associated with bone and cartilage at the site of injury, consequently facilitating the development of HO, which was thought to be associated with the activation of the Wnt/β-catenin pathway.

Conclusion

MIF, which mediates the ROS/HIF-1α/MIF positive feedback loop during the hypoxic phase of HO, triggers the Wnt/β-catenin signaling pathway to enhance the osteogenic differentiation and formation of HO in TDSCs.

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巨噬细胞迁移抑制因子通过介导 ROS/HIF-1α 正反馈回路和激活 Wnt/β-catenin 信号通路促进异位骨化。

背景：异位骨化（HO）是指骨骼系统以外的部位出现骨组织。骨骼系统的发育和成熟受巨噬细胞迁移抑制因子（MIF）的显著影响。本研究的目的是通过涉及 ROS/HIF-1α/MIF 的正反馈回路，研究 MIF 对肌腱衍生干细胞（TDSCs）体外成骨分化和矿化的影响：方法：从 C57/BL6 小鼠后肢中分离并鉴定出 TDSCs。方法：从 C57/BL6 小鼠后肢中分离鉴定出 TDSCs，并在体外研究了 MIF 在 HO 中的功能性和程序性作用，重点研究了 MIF 对 TDSCs 分化为骨形成细胞的影响。75只小鼠被随机分为五组。对 MIF 及其受体进行基因表达和组织学分析，并确定体内成骨标志物的表达：结果表明，MIF 对 TDSCs 的成骨分化具有积极的浓度依赖性作用。此外，在模拟早期创伤缺氧微环境中发现了ROS/HIF-1α/MIF正循环，导致MIF表达水平增加3至4倍。研究还发现，MIF能使损伤部位与骨和软骨相关的标志物的表达水平提高一倍，从而促进HO的发展，这被认为与Wnt/β-catenin通路的激活有关：结论：MIF在HO的缺氧阶段介导ROS/HIF-1α/MIF正反馈环，触发Wnt/β-catenin信号通路，促进TDSCs的成骨分化和HO的形成。

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.