KPT-330 alleviates osteoarthritis by inhibiting subchondral bone osteoclastogenesis via the NF-κB and MAPK signaling pathways

Summary Osteoclast-driven subchondral bone remodeling is a critical driver of osteoarthritis (OA) progression. While exportin-1 (XPO1) inhibitors demonstrate anti-osteoclastogenic potential in cancers, their therapeutic utility in OA remains unexplored. We hypothesized that selective XPO1 inhibition by KPT-330 suppresses osteoclastogenesis to ameliorate OA. In destabilization of the medial meniscus (DMM)-induced OA mice, KPT-330 reversed subchondral bone loss, preserved cartilage integrity, and reduced osteoclast numbers. In vitro, KPT-330 (≤50 nM) non-toxically inhibited RANKL-induced osteoclast differentiation and bone resorption. Mechanistically, KPT-330 suppressed p65 phosphorylation/nuclear translocation and attenuated MAPK signaling (p38, ERK1/2, and JNK), thereby downregulating osteoclastogenic transcription factors c-Fos and NFATc1. These findings establish XPO1 inhibition as a potential dual-action strategy targeting osteoclast-mediated bone-cartilage crosstalk in OA.