Interleukin-1 Receptor-Associated Kinase 3 Attenuates Chondrocyte Senescence and Osteoarthritis via Inhibition of the TLR7/9-NF-κB Axis

Osteoarthritis (OA) is a common degenerative joint disorder associated with aging, marked by chondrocyte senescence, cartilage degradation, and chronic inflammation. Although cellular senescence significantly contributes to OA progression, the molecular mechanisms governing this process are not fully understood. Interleukin-1 receptor-associated kinase 3 (IRAK3) acts as a negative regulator of Toll-like Receptor (TLR) signaling; however, its role in OA and chondrocyte senescence remains unclear. We employed bioinformatics analysis, human OA cartilage samples, a destabilization of the medial meniscus (DMM) mouse model, and in vitro assays in ATDC5 chondrocytes to explore the expression and functional role of IRAK3 in OA. To evaluate senescence, mitochondrial function, Reactive Oxygen Species (ROS), and inflammatory signaling, we conducted gain- and loss-of-function experiments alongside biochemical and histological analyses. IRAK3 expression was markedly reduced in both human and murine osteoarthritis (OA) cartilage. Silencing IRAK3 intensified hydrogen peroxide-induced senescence, mitochondrial dysfunction, Reactive Oxygen Species (ROS) production, and catabolic metabolism, whereas its overexpression offered protective effects. Mechanistically, IRAK3 inhibited the TLR7/TLR9–NF-κB pathway, leading to decreased secretion of pro-inflammatory cytokines and reduced chondrocyte senescence. In vivo, intra-articular injection of adeno-associated virus (AAV) to knock down IRAK3 can promote the progression of OA in DMM mice. IRAK3 serves as a crucial inhibitor of chondrocyte senescence and the progression of osteoarthritis (OA) by reducing TLR-mediated inflammation and oxidative stress. These findings highlight IRAK3 as a promising therapeutic target for addressing senescence-related osteoarthritis.