M2-exo promote orthodontic bone remodeling via the MeCP2-TCF20-HDAC1 axis.

BACKGROUND: Orthodontic bone remodeling is a complex process involving a dynamic balance between osteogenesis and osteoclast genesis. Although M2 macrophage-derived exosomes (M2-exos) have emerged as key regulators of bone metabolism through immunomodulation and paracrine signaling, their specific mechanisms in orthodontic tooth movement (OTM) remain unclear. This study aimed to investigate the role of the epigenetic MeCP2-TCF20 complex in M2-exo-mediated orthodontic bone remodeling. METHODS: A rat OTM model was established to evaluate bone remodeling dynamics using micro-CT, histomorphometry (H&E and TRAP staining), and immunohistochemistry. Periodontal ligament stem cells (PDLSCs) were isolated and treated with M2-exos to assess osteogenic differentiation through alkaline phosphatase (ALP) and alizarin red S (ARS) staining, qPCR, and Western blot. Molecular mechanisms were explored via RNA sequencing (RNA-seq), immunoprecipitation-mass spectrometry (IP-MS), and functional validation experiments (siRNA knockdown and overexpression). RESULTS: Orthodontic tension force upregulate M2 polarization and osteoblast differentiation, in contrast to compressive force which triggered M1 polarization and osteoclastogenesis, with concomitant modulation of MeCP2 expression in mechanically stressed periodontal tissues. M2-exos significantly promoted the proliferation and osteogenic differentiation of PDLSCs. Mechanistic studies revealed that M2-exos activated the MeCP2-TCF20 complex, which directly suppressed HDAC1 expression, thereby activating the Wnt/β-catenin signaling pathway. CONCLUSION: These findings highlight the critical role of the M2-exo/MeCP2-TCF20 axis in orchestrating orthodontic bone remodeling through epigenetic regulation. This study provides novel insights into the therapeutic potential of M2-exos for enhancing orthodontic treatment efficiency.