Porphyromonas gingivalis extracellular vesicles exacerbated osteoporosis by disrupting osteoblast mitochondrial dynamics and inhibiting Cpt2-regulated fatty acid oxidation

Background Recent studies have implicated periodontitis (PD) as a potential risk factor for osteoporosis; however, the precise mechanisms remain unclear. Porphyromonas gingivalis ( Pg ), a key pathogen associated with PD, can secrete extracellular vesicles (EVs). However, whether Pg EVs can be transported to the bone marrow and influence osteoporosis-related osteoblast differentiation warrants exploration. This study compares Pg EVs with EVs from  Porphyromonas endodontalis  ( Pe ), which is a less virulent congener but the evidence for its pathogenicity in PD is weak. Results Pg EVs can be translocated into the marrow of mice and be internalized by osteoblasts through clathrin- and lipid raft-mediated endocytosis, thereby exacerbating osteoporosis. Pg EVs promote mitochondrial fission and inhibit mitochondrial fusion, leading to mitochondrial fragmentation, impaired mitochondrial activity and suppressed osteogenic differentiation. Furthermore, Pg EVs downregulate the protein level of carnitine palmitoyl transferase 2 (Cpt2) and inhibit fatty acid oxidation (FAO) by disrupting mitochondrial dynamics, which impairs osteoblast ATP production and exacerbates osteoporosis. The effects of Pe EVs are similar but weaker than those of Pg EVs. Conclusions This study elucidates that Pg EVs exacerbate osteoporosis by disrupting osteoblast mitochondrial dynamics and suppressing Cpt2-regulated FAO. This study contributes to understanding of the etiological mechanisms through which Pg contributes to the progression of osteoporosis and highlights the pivotal role of EVs in the association between periodontal disease and systemic diseases. Graphical