Mechanical stretch promotes osteogenesis in the midpalatal suture by enhancing neutrophil fatty acid oxidation through the S1PR1/STAT3 axis.

In clinical maxillary arch constriction, selecting an optimal initial distraction force may help reduce relapse associated with insufficient suture osteogenesis. Neutrophils play a crucial role in early suture osteogenesis; however, how initial distraction force regulates their function remains unclear. Therefore, this study investigated how different magnitudes of initial distraction force modulate neutrophil activity and influence suture osteogenesis. By integrating an in vivo maxillary expansion model in 6-week-old male C57BL/6 mice with flow cytometric sorting, transcriptomic analysis, and an in vitro three-dimensional stretching model, this study systematically characterized the functional and metabolic changes of neutrophils under different mechanical conditions and further explored the underlying regulatory mechanisms. The findings demonstrate that neutrophils serve as important mediators of force-dependent osteogenesis and contribute to force-dependent differences in osteogenesis during midpalatal expansion. Different magnitudes of distraction force induced metabolic divergence in intra-sutural neutrophils, leading to differential regulation of their energy metabolism and osteogenic potential. Mechanistically, mechanical tension enhanced fibroblast-derived S1P secretion via modulation of SPHK1 activity, which activated the S1PR1/STAT3 signaling pathway in neutrophils, promoted fatty acid oxidation, and ultimately drove their pro-osteogenic function. These results clarify how initial distraction force regulates the mechanics-immunometabolism-osteogenesis axis and provide a framework in which fibroblast-derived S1P and matrix stiffness coordinate neutrophil S1PR1-STAT3-FAO signaling to promote osteogenesis.