Division of Spine Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China; Academy of Orthopedics, Guangzhou, China.
Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China; Academy of Orthopedics, Guangzhou, China.
Bone. 2025 Jan;190:117331. doi: 10.1016/j.bone.2024.117331. Epub 2024 Nov 15.
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.
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.
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.
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.
异位骨化（HO）是指骨骼系统以外的部位形成骨组织。巨噬细胞移动抑制因子（MIF）对骨骼系统的发育和成熟有显著影响。本研究旨在探讨 MIF 通过 ROS/HIF-1α/MIF 正反馈环对肌腱衍生干细胞（TDSCs）成骨分化和矿化的影响。
从小鼠后肢分离和鉴定 TDSCs。体外研究 MIF 在 HO 中的功能和程序作用，重点研究 MIF 对 TDSCs 向成骨细胞分化的影响。75 只小鼠随机分为 5 组。体内检测 MIF 及其受体的基因表达和组织学分析，以及确定成骨标志物的表达。
结果显示 MIF 对 TDSCs 成骨分化具有正向且浓度依赖性的影响。此外，在模拟早期创伤缺氧微环境中检测到 ROS/HIF-1α/MIF 正反馈环，导致 MIF 表达水平增加 3 至 4 倍。MIF 还被发现增强了与损伤部位骨和软骨相关标志物的表达水平，从而促进了 HO 的发展，这被认为与 Wnt/β-catenin 信号通路的激活有关。
MIF 在 HO 的缺氧相期间介导 ROS/HIF-1α/MIF 正反馈环，触发 Wnt/β-catenin 信号通路，增强 TDSCs 中的成骨分化和 HO 的形成。
