OPG/RANKL modulates NLRP3 mediated neuroinflammation and protects dopaminergic neurons in parkinson’s disease

Parkinson’s disease (PD) is the second most common neurodegenerative disorder, with neuroinflammation as a key pathogenic mechanism. Osteoporosis is a frequent comorbidity and non-motor feature of PD, and growing evidence indicates that bone-derived factors play significant role in brain. Osteoprotegerin (OPG) and receptor activator of nuclear factor kappa-B ligand (RANKL) are key regulators of bone metabolism and inflammation. Our previous study showed reduced plasma OPG levels in PD patients, but the underlying mechanisms remain unclear. Thus, our study employed integrated in vivo and in vitro approaches to investigate the role of the OPG/RANKL axis in PD. Behavioral tests were used to assess motor function in PD mice, followed by western blotting, immunofluorescence, multiplex assay and metabolomics to evaluate dopaminergic neuron loss and inflammatory responses. In addition, Rankl ⁺/⁻ and Nlrp3 ⁻/⁻ mice were used to further explore the underlying mechanisms. Our results showed that OPG suppressed lipopolysaccharide induced neuroinflammation in BV2 microglia, whereas RANKL stimulation increased pro-inflammatory cytokine expression and activated the NLRP3 inflammasome. In vivo, OPG exerted significant neuroprotective effects, while RANKL overexpression aggravated behavioral deficits, neuroinflammation, and dopaminergic neuron loss. Consistently, Rankl +/− mice showed reduced neuroinflammation and neuronal damage. Mechanistically, NLRP3 knockout markedly attenuated RANKL induced neuroinflammation and dopaminergic neurodegeneration, indicating that RANKL promotes PD progression via NLRP3 dependent pathways. Moreover, RANKL activated cGAS–STING signaling to regulate NLRP3 inflammasome activation, thereby mediating neuroinflammation. Overall, the OPG/RANKL axis contributes to PD pathogenesis through cGAS–STING/NLRP3 mediated neuroinflammation and may represent a potential therapeutic target.