Glibenclamide attenuates osteoarthritis by suppressing NLRP3 inflammasome activation in synovial macrophages through the MAPK pathway.

BACKGROUND

Osteoarthritis (OA) is a chronic joint disorder characterized by progressive cartilage degeneration, synovial inflammation, and abnormal subchondral bone remodeling. Synovial macrophages play a key role in regulating joint inflammation and cartilage destruction. Glibenclamide (Gb) is a commonly used hypoglycemic drug that also has a significant anti-inflammatory effect, while its potential role in OA remains unexplored.

METHODS

For in vivo experiments, destabilization of the medial meniscus (DMM) induced mouse OA model was employed to evaluate the effects of Gb on OA progression. Synovial inflammation and cartilage damage were assessed histologically. For in vitro experiments, western bolt and qRT-PCR were used to detect the effect of Gb on macrophage inflammation. Furthermore, a co-culture system was constructed to investigate the effect of Gb on chondrocytes. To explore the mechanism of Gb regulating macrophage inflammation, RNA sequencing was performed. Additionally, in vivo targeted knockdown of NLRP3 in synovial macrophages was performed to validate the mechanism of Gb.

RESULTS

Oral administration of Gb significantly attenuated OA progression in the DMM induced OA model, as evidenced by reduced synovitis, preserved cartilage damage, and decreased osteophyte formation and subchondral bone ossification. Gb treatment reduced synovial macrophage infiltration, promoted a shift from pro-inflammatory M1 to anti-inflammatory M2 phenotype, lowered IL-1β and TNF-α levels, and restored IL-10 expression. Mechanistically, Gb inhibited MAPK signaling and disrupted the NEK7–NLRP3 interaction, leading to suppression of NLRP3 inflammasome activation. In the macrophage–chondrocyte co-culture system, Gb enhanced chondrocyte extracellular matrix synthesis, proliferation, and migration, while reducing apoptosis, through regulation of macrophage activity. Importantly, the protective effects of Gb were weakened upon targeted knockdown of NLRP3 in synovial macrophages, confirming the dependence of its function on macrophage NLRP3 inflammasome.

CONCLUSION

This study demonstrates that Gb attenuates OA progression by targeting the MAPK–NLRP3 inflammasome axis in synovial macrophages, regulating synovial inflammation and preserving chondrocyte function. These findings reveal a previously unrecognized mechanism by which Gb attenuates OA progression and provide a theoretical supporting for its potential use as a therapeutic agent for OA.