Kongensin A targeting PI3K attenuates inflammation-induced osteoarthritis by modulating macrophage polarization and alleviating inflammatory signaling

The inflammatory microenvironment, polarization of macrophages towards the M1 phenotype, and consequent matrix degradation and senescence of chondrocytes are primary contributors to the degeneration of knee joint cartilage, further exacerbating the progression of osteoarthritis (OA). Kongensin A (KA) is a recently identified natural plant extract exhibiting anti-necrotic apoptosis and anti-inflammatory properties, but the potential efficacy in alleviating OA remains uncertain. The current research lucubrated the effect of KA on the inflammatory microenvironment and macrophage polarization, as well as its regulatory function in extracellular matrix (ECM) metabolism and chondrocyte senescence. Our findings demonstrated that KA can suppress inflammatory signaling, maintain homeostasis between ECM anabolism and catabolism, and suppress chondrocytes senescence. Further investigation elucidated that the mechanism involves the suppression of the PI3K/AKT/NF-κB axis in chondrocytes under inflammatory conditions. Moreover, KA impeded M1 polarization of macrophages via inhibiting PI3K/AKT/NF-κB axis. Subsequently, we treated chondrocytes with macrophages-derived conditioned medium (CM) and revealed that KA can promote ECM anabolism and alleviate chondrocytes senescence by reprogramming macrophage polarization. Consistent with in vitro experiments, in vivo administration of KA demonstrated alleviated cartilage degeneration and delayed progression of OA. Collectively, through obstructing the PI3K/AKT/NF-κB axis, KA can reprogram macrophage polarization, promote matrix metabolism equilibrium, and alleviate chondrocytes senescence, thereby attenuating the pathology of OA. In conclusion, KA may emerge as a promising therapy for OA.