Paroxetine as a Therapeutic Agent in Inflammatory Osteolysis: Mechanistic Insights and Efficacy.

Inflammatory osteolysis is a common feature of numerous orthopedic conditions, primarily driven by excessive osteoclast formation and activation. Recent studies have demonstrated that paroxetine, a selective serotonin reuptake inhibitor commonly prescribed for mental disorders, has significant anti-inflammatory effects. However, its effects on inflammatory osteolysis have not been fully elucidated. In this study, we investigated the effects and underlying mechanisms of paroxetine on osteoclast differentiation and function as well as its influence on inflammatory osteolysis in a murine model. A mouse model of LPS-induced osteolysis was developed to assess the therapeutic efficacy of paroxetine in vivo. Utilizing the molecular structure of paroxetine, network pharmacology was used to predict principal targets and underlying mechanisms. The effect of paroxetine on osteoclast biology was subsequently investigated using morphological analysis, quantitative PCR (qPCR), and Western blotting. The findings from animal experiments demonstrated that paroxetine effectively mitigated LPS-induced bone loss by inhibiting osteoclast differentiation. In vitro analyses revealed that paroxetine suppresses osteoclast formation and bone resorption in a dose-dependent manner. Mechanistically, paroxetine downregulated osteoclast-specific genes and proteins while concurrently inhibiting the NF-κB and PI3K-AKT signaling pathways. Additionally, network pharmacology analysis identified PIK3CA as a pivotal target, substantiated by molecular docking studies (binding energy of -8.0 kcal/mol) and rescue experiments employing PI3K (740 Y-P) and AKT (SC79) agonists, which reversed paroxetine-mediated inhibition of osteoclast formation. Paroxetine attenuated LPS-induced inflammatory osteolysis in mice and suppressed osteoclast differentiation and function in vitro, an effect associated with down-regulation of NF-κB and PI3K-AKT signaling. These data indicate that paroxetine may represent a potential therapeutic candidate for osteolytic bone diseases. However, further validation is required to confirm its efficacy and safety in more complex pre-clinical models and in humans.