Kojic acid alleviates osteoarthritis by attenuating inflammation and restoring impaired autophagy through regulating NF-κB and PI3K/AKT/mTOR signaling pathways: An in vivo and in vitro study

Background: Osteoarthritis (OA) is the most prevalent joint disorder globally, causing a substantial and increasing socioeconomic burden. Kojic acid (KA) presented potential biological roles in regulating inflammation and autophagy, which was implicated in OA progression. However, its role in chondrocytes and OA has not been reported. To do so, this study aims to explore the chondroprotective effect of KA and elucidate its regulatory mechanisms.

Methods: IL-1β in vitro was used to induce OA-like phenotypes. Cell viability was measured by cell counting kit-8 assay. RT-qPCR, western blotting, as well as immunofluorescence staining were used to assess protein and RNA expression of inflammatory (COX2 and iNOS), catabolic (MMP13 and MMP3), anabolic (collagen II, aggrecan and SOX9), and signaling pathways factors. Destabilized medial meniscus (DMM) surgery was adopted to build OA model in vivo. After consecutive 8 weeks of intra-articular injection of KA, X-ray, μ-CT, histological staining, as well as immunohistochemistry staining were adopted to evaluate effects of KA on articular cartilage in vivo.

Results: KA did not affect chondrocyte viability. KA notably elevated anabolic factors expression, simultaneously, inhibited catabolic and inflammatory factors expression in vitro. Mechanistically, KA significantly suppressed the activated NF-κB and PI3K/AKT/mTOR signaling pathways. Moreover, impaired autophagy was restored by KA. Inhibition of autophagy by 3-MA diminished the chondroprotective effect of KA. Intra-articular injection of KA can significantly alleviate DMM-induced cartilage damage in vivo.

Conclusion: Collectively, our work is the first to demonstrate that KA can alleviate osteoarthritis by attenuatinginflammationand restoring impaired autophagy through regulating relevant signaling pathways. This in vivo and in vitro study provides strong evidence supportingKA as a novel and valuable approach for treating OA.