Mechanical force-induced oncostatin M secretion by Jun-positive neutrophils promotes craniofacial bone regeneration for midface hypoplasia treatment.

Abstract

Background: Midfacial hypoplasia is a common craniofacial deformity. Trans-sutural distraction osteogenesis (TSDO), which applies mechanical force to stimulate bone formation at the zygomaticomaxillary sutures (ZMS), has emerged as an effective therapeutic strategy. However, the underlying mechanisms of TSDO-induced osteogenesis remain unclear, resulting in prolonged treatment durations and limited clinical application.

Methods: A TSDO model was established in 4-week-old C57BL/6 mice and neutrophil-depleted mice to investigate the role of neutrophils in bone regeneration at the ZMS. Single-cell RNA sequencing was used to characterize neutrophil dynamics and heterogeneity during TSDO, and intercellular signaling pathways were identified through CellChat analysis. Additionally, in vitro stretching experiments using differentiated HL-60 cells were performed to assess the mechanosensitive behavior of neutrophils.

Results: In the TSDO model, mechanical distraction significantly increased neutrophil infiltration in the ZMS and surrounding bone marrow. Neutrophil depletion impaired distraction-induced bone formation. Single-cell sequencing revealed that the Jun⁺ neutrophil subset (Jun-Neu) facilitated the osteogenic differentiation of suture-derived stem cells (SuSCs) via secretion of oncostatin M (OSM). In vitro, mechanical stretching (10%, 0.5 Hz) activated the phosphoinositide 3-kinase (PI3K)-AKT pathway in neutrophils, enhancing OSM release and promoting the osteogenic differentiation of SuSCs.

Conclusions: This study identifies a mechanical force-neutrophil-bone regeneration axis in TSDO, highlighting the critical role of Jun-Neu-derived OSM in promoting osteogenesis. These findings provide theoretical insights for optimizing TSDO-based clinical strategies.