NEK2 promotes the progression of osteoarthritis by stabilizing ATF2 through phosphorylation at Ser-112 and inhibiting autophagy

NEK2 (NIMA-related kinase 2) has recently gained attention for its potential role in osteoarthritis (OA) chondrocytes, however, its specific involvement remains unclear. This study aimed to investigate the role of NEK2 in OA progression and the underlying molecular mechanisms. Primary mouse knee chondrocytes were stimulated with IL-1β to establish an in vitro OA model, followed by the knockdown of NEK2 or ATF2. The results indicated that silencing NEK2 or ATF2 impeded the IL-1β-induced decrease in cell proliferation and increase in inflammation, extracellular matrix (ECM) degradation, and apoptosis in chondrocytes. NEK2 or ATF2 knockdown restored IL-1β-induced autophagy defects. Mechanistically, NEK2 interacts with ATF2 to reduce its ubiquitylation level and enhance its stability by phosphorylating ATF2 at Ser-112. Consistently, ATF2 overexpression reversed the protective effect of NEK2 silencing on IL-1β-induced autophagy defects and chondrocyte injury. Additionally, a mouse OA model was established using medial meniscus destabilization (DMM) surgery, and NEK2 was knocked down by intra-articular injection of an adenovirus-mediated NEK2 interference vector. Downregulation of NEK2 mitigated cartilage degradation andautophagy defects ina mouse OA model. In conclusion, NEK2 promoted OA progression by enhancing ATF2 stability by phosphorylating it at Ser-112.