KLF5⁺ neutrophils mediate alveolar bone resorption through fibroblast dysfunction under mechanical loading

Nan Ge¹Linsha Ma²Song Li^1*

• ¹Beijing Stomatological Hospital, Capital Medical University, Beijing, China
• ²Capital Medical University Affiliated Beijing Friendship Hospital Beijing Institute of Clinical Medicine, Beijing, China

Orthodontic tooth movement (OTM) relies on mechanical force–induced alveolar bone remodeling, yet the underlying cellular and molecular mechanisms remain incompletely understood. Here, we applied graded orthodontic forces (0 g, 25 g, 50 g, 100 g) in rats and identified 50 g as the optimal force that maximizes tooth movement while preserving bone integrity. In contrast, excessive force (100 g) triggered severe bone loss and heightened inflammatory cytokine expression. To explore the underlying mechanisms, single-cell RNA sequencing of alveolar bone tissues revealed a marked expansion of mature neutrophils and depletion of fibroblasts under 50 g loading. Among neutrophils, a distinct KLF5⁺ subset emerged, exhibiting elevated pro-inflammatory and osteoclastogenic gene expression. Concurrently, fibroblasts under mechanical stress showed enhanced inflammatory and apoptotic signaling, reduced proliferative capacity, and increased ligand–receptor interactions with KLF5 ⁺ neutrophils. Functionally, KLF5-overexpressing neutrophil-like cells impaired fibroblast viability and promoted osteoclastogenic signaling, while KLF5 silencing reversed these effects. Collectively, our findings reveal a KLF5⁺ neutrophil subset as a critical mediator of force-induced inflammatory remodeling and fibroblast dysfunction, highlighting neutrophil KLF5 as a potential therapeutic target to optimize OTM and prevent pathological bone loss.