Lei Ming, Liu Boyu, Wan Baicheng, Feng Yanbin, Teng Yilin, Xi Deshuang, Zeng Gaofeng, Zong Shaohui
Department of Spine Osteopathia, The First Affiliated Hospital of Guangxi Medical University, Guangxi Medical University, No. 6, Shuangyong Road, Nanning, 530021, Guangxi, China.
Department of Bone and Joint Surgery, The Fifth Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China.
Eur J Med Res. 2025 Aug 5;30(1):713. doi: 10.1186/s40001-025-02993-7.
Critical-sized bone defects, characterized by poor spontaneous healing capacity, remain a common clinical challenge, and stem cell and gene therapies are key strategies for bone repair and regeneration. Transcription factor 7-like 2 (TCF7L2) is a key regulator of the Wnt signaling pathway, with potential applications in gene editing. However, the role of TCF7L2 in the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) remains poorly understood. We knocked down or overexpressed TCF7L2 to evaluate its effect on erastin-induced ferroptosis in BMSCs. Simultaneously, we assessed the impact of TCF7L2 overexpression on the osteogenic capacity of BMSCs. To confirm the involvement of glutathione peroxidase 4 (GPX4), we conducted rescue experiments by knocking down GPX4 expression. A mouse cranial defect model was established to analyze the effect of TCF7L2 overexpression on cranial bone healing. The results showed that TCF7L2 knockdown promoted, while TCF7L2 overexpression inhibited, erastin-induced ferroptosis in BMSCs. Mechanistic studies revealed that TCF7L2 knockdown reduced, while TCF7L2 overexpression enhanced, GPX4 expression, thereby regulating ferroptosis. Conversely, GPX4 knockdown significantly attenuated the regulatory effects of TCF7L2 overexpression on cell proliferation and ferroptosis inhibition. Furthermore, TCF7L2 overexpression promoted cell proliferation, osteogenic differentiation, and mineralization in vitro, while enhancing cranial defect healing in vivo. This study is the first to reveal the dual role of TCF7L2: regulating ferroptosis in BMSCs via GPX4, while promoting BMSC proliferation and osteogenic differentiation. These findings provide novel molecular targets and theoretical foundations for the treatment of bone defects.
临界尺寸骨缺损以自发愈合能力差为特征，仍然是一个常见的临床挑战，而干细胞和基因疗法是骨修复和再生的关键策略。转录因子7样2（TCF7L2）是Wnt信号通路的关键调节因子，在基因编辑中有潜在应用。然而，TCF7L2在骨髓间充质干细胞（BMSC）成骨分化中的作用仍知之甚少。我们敲低或过表达TCF7L2以评估其对BMSC中erastin诱导的铁死亡的影响。同时，我们评估了TCF7L2过表达对BMSC成骨能力的影响。为了证实谷胱甘肽过氧化物酶4（GPX4）的参与，我们通过敲低GPX4表达进行了挽救实验。建立小鼠颅骨缺损模型以分析TCF7L2过表达对颅骨愈合的影响。结果表明，敲低TCF7L2促进，而过表达TCF7L2抑制BMSC中erastin诱导的铁死亡。机制研究表明，敲低TCF7L2降低，而过表达TCF7L2增强GPX4表达，从而调节铁死亡。相反，敲低GPX4显著减弱了TCF7L2过表达对细胞增殖和铁死亡抑制的调节作用。此外，TCF7L2过表达促进体外细胞增殖、成骨分化和矿化，同时增强体内颅骨缺损愈合。本研究首次揭示了TCF7L2的双重作用：通过GPX4调节BMSC中的铁死亡，同时促进BMSC增殖和成骨分化。这些发现为骨缺损的治疗提供了新的分子靶点和理论基础。
