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

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 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. 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. 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.