Magnesium-based implants accelerate femoral fracture healing through promoting histone lactylation-mediated osteoclastogenesis inhibition
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
Abstract
To investigate the molecular mechanisms by which magnesium (Mg)-based implants, specifically Mg-containing intramedullary nails (Mg-IMNs), promote femoral fracture healing. Rats with femoral fractures were treated with Mg-IMNs. In vitro experiments were conducted to assess the impact of Mg 2+ 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. Mg-IMNs significantly enhanced fracture healing by inhibiting osteoclastogenesis. Mg 2+ 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. This study uncovers a novel mechanism by which Mg 2+ promotes fracture healing through histone lactylation-mediated inhibition of osteoclastogenesis. These findings offer new therapeutic strategies for enhancing fracture repair via epigenetic regulation. • Magnesium implants promote femoral fracture healing via osteoclastogenesis inhibition. • Mg 2+ enhances histone lactylation to suppress osteoclast maturation. • The P300/H3K18LA/HDAC1 pathway mediates Mg 2+ -induced epigenetic regulation. • Lactate mimics the healing effects of magnesium in vivo. • Findings provide a novel therapeutic strategy for improving fracture repair.