Bone marrow mesenchymal stem cell-derived apoptotic bodies alleviate periodontitis-associated alveolar bone...

Periodontitis is a prevalent chronic inflammatory disease characterized by an imbalance between osteoclast-mediated bone resorption and osteoblast-mediated bone formation. Bone marrow mesenchymal stem cells (BMMSCs) are essential for periodontal regeneration; however, the inflammatory periodontal microenvironment can rapidly induce BMMSC apoptosis. Apoptotic bodies (ABs), the major vesicular products released by apoptotic cells, have recently emerged as bioactive mediators of intercellular communication. Nevertheless, whether ABs derived from inflammation-primed BMMSCs retain regulatory functions and contribute to periodontal bone remodeling remains unclear. In this study, we investigated the effects of BMMSC-derived ABs on osteogenic differentiation and alveolar bone resorption. ABs generated from TNF-α-stimulated BMMSCs were characterized and co-cultured with recipient BMMSCs under osteogenic conditions. In vivo, a ligature-induced periodontitis mouse model was established, and ABs were locally administered into the gingival sulcus to evaluate their therapeutic effects. We found that inflammatory stimulation induced caspase-dependent apoptosis in BMMSCs and promoted AB generation. These ABs were efficiently internalized by recipient BMMSCs and significantly enhanced osteogenic differentiation and mineralization in vitro. Local administration of ABs markedly attenuated alveolar bone resorption and increased osteogenic marker expression in periodontal tissues. Proteomic analysis further identified ZBTB16 as a critical functional cargo enriched in ABs, and knockdown of ZBTB16 abolished the pro-osteogenic and bone-protective effects of ABs. Collectively, these findings demonstrate that BMMSC-derived ABs promote osteogenesis by transferring ZBTB16, thereby alleviating periodontitis-associated alveolar bone resorption. This study provides new evidence supporting AB-based cell-free therapy for periodontal bone regeneration.