Abstract
Transcriptomics studies have identified integrin receptor β2 subunit (ITGB2) as a core gene in osteoarthritis (OA), strongly linked to osteoclast function in the subchondral bone. However, the mechanism through which ITGB2 regulates osteoclast function in OA remains unclear. In this study, we found that ITGB2 was negatively correlated with ITGB1 in the human subchondral bone. Proteomic analysis indicated that integrin binding is crucial in OA subchondral bone, with ITGB2 identified as a significantly upregulated protein in OA. In vitro experiments using immunoprecipitation and bimolecular fluorescence complementation revealed that ITGB2, but not ITGB1, directly interacts with Rac1 during osteoclast differentiation. Activated Rac1 promotes osteoclast differentiation and bone resorption through several mechanisms. ITGB2 knockdown reduced Rac1-GTP levels and increased ITGB1 expression. ITGB2 inhibition reduced actin ring formation and microtubule migration to the cell edge during osteoclast differentiation. Additionally, overexpression of ITGB1 in ITGB2-knockdown cells not only further suppressed ITGB2 expression but also exacerbated the inhibition of osteoclast differentiation. In a DMM mouse model, ITGB2 was associated with osteoclast activity in the subchondral bone. ITGB2 knockdown significantly reduced bone resorption and slowed OA progression by inhibiting osteoclastogenesis. In conclusion, our study identified a novel mechanism for the reciprocal regulation of integrin subunits. Moreover, inhibition of the ITGB2 signalling pathway slows subchondral bone remodelling in osteoarthritis by inhibiting osteoclast differentiation, offering a potential strategy for targeted therapeutic interventions.