Kukoamine A protects mice against osteoarthritis by inhibiting chondrocyte inflammation and ferroptosis via SIRT1/GPX4 signaling pathway

Abstract

Aims: Osteoarthritis (OA) is one of the common chronic degenerative joint diseases, characterized by cartilage damage, subchondral bone changes, osteophyte formation, and synovitis. Kukoamine A (KuKA) is a bioactive compound isolated from Lycium chinense which is known as its anti-inflammatory activity. In this study, we detected the regulatory role of KuKA on OA both in vivo and in vitro.

Materials and methods: Mouse chondrocytes were cultured and mouse model of OA was established. Inflammatory mediator was measured by ELISA. The signaling pathway was tested by western blot analysis.

Key findings: KuKA inhibited IL-1β-induced PGE2 and NO production and iNOS and COX-2 expression. IL-1β-induced MMP1 and MMP3 production was attenuated by KuKA. IL-1β-induced MDA, iron, and ROS were alleviated by KuKA. Meanwhile, GSH content, GPX4, Ferritin, SIRT1, Nrf2, and HO-1 expression were upregulated by KuKA. Furthermore, the inhibitory role of KuKA on IL-1β-induced inflammation, MMPs production, and ferroptosis were reversed by SIRT1 inhibitor. In vivo, KuKA could attenuate OA development in mouse model. KuKA markedly alleviated MMP1, MMP3, iNOS, and COX2 expression in OA mice.

Significance: In conclusion, KuKA could inhibit OA development through suppressing chondrocyte inflammation and ferroptosis via SIRT1/GPX4 signaling pathway.

Keywords: Ferroptosis; Inflammation; Kukoamine A; Osteoarthritis; SIRT1.