Background
Periodontitis is the leading cause of tooth loss in adults due to progressive bone destruction, which is closely related to the dysfunction of bone mesenchymal stem cells (BMSCs). Existing evidence suggests that mitochondrial disorders are associated with periodontitis. However, whether mitochondrial dysregulation contributes to the osteogenic impairment of BMSCs and the underlying mechanisms remain unclear. Macrophages have been shown to communicate extensively with BMSCs in periodontitis. Recent studies have reported a novel manner of cellular communication in which mitochondria-rich extracellular vesicles（MEVs） transfer mitochondria from parent cells to recipient cells, playing a role in both physiological and pathological conditions. Therefore, we aimed to investigate the role of MEVs in orchestrating the crosstalk between macrophages and BMSCs in periodontitis to formulate management strategies for bone loss.
Conclusions
The transfer of mitochondria to BMSCs via MEVs exacerbates alveolar bone resorption through LCN2/OMA1/OPA1 signaling in periodontitis. Inhibition of LCN2 alleviates inflammatory bone loss, suggesting a promising therapeutic strategy for periodontitis.
Results
Our results revealed that macrophages underwent significant mitochondrial dysfunction and inflammation in periodontitis and that MEVs derived from these macrophages played a role in alveolar bone destruction. Furthermore, cell imaging showed that inflammatory macrophages packaged numerous damaged mitochondria into MEVs, and the entry of these impaired mitochondria into BMSCs disrupted mitochondrial dynamics and hindered donut-shaped mitochondria formation, leading to osteogenic dysfunction. Proteomic analysis revealed that the proteins enriched in macrophage-derived MEVs were largely related to mitochondria and the formation and transport of vesicles. Additionally, we found that MEVs from macrophages significantly increased lipocalin 2 (LCN2) in BMSCs in periodontitis and that LCN2 perturbed mitochondrial morphological changes in BMSCs by inducing the degradation of OMA1 and accumulation of OPA1, resulting in osteogenesis impairment in BMSCs. Inhibition of LCN2 rescued the osteogenic dysfunction of BMSCs and alveolar bone loss in periodontitis. Conclusions: The transfer of mitochondria to BMSCs via MEVs exacerbates alveolar bone resorption through LCN2/OMA1/OPA1 signaling in periodontitis. Inhibition of LCN2 alleviates inflammatory bone loss, suggesting a promising therapeutic strategy for periodontitis.