Sappanone a alleviates osteoarthritis progression by inhibiting chondrocyte ferroptosis via activating the SIRT1/Nrf2 signaling pathway.

Osteoarthritis (OA) is a common degenerative joint disease that cause pain and disability in adults. Chondrocyte ferroptosis is found to be involved in OA progression. Sappanone A has been found as an anti-inflammatory and antioxidative agent in several diseases. This study aims to investigate the effects of sappanone A on OA progression and chondrocyte ferroptosis. IL-1ß-induced chondrocytes and destabilization of the medial meniscus (DMM)-induced rats were respectively used as the OA model in vitro and in vivo. The effects of sappanone A on inflammation, extracellular matrix (ECM) metabolism, and ferroptosis were determined. Our results showed that in IL-1ß-induced chondrocytes, sappanone A suppressed the production of NO, PGE2, TNF-α, IL-6, iNOS, and COX2. Sappanone A also inhibited the expression of MMP3, MMP13, and ADAMTS5, while increasing collagen II expression. Moreover, sappanone A alleviated cytotoxicity and decreased the levels of intracellular ROS, lipid ROS, MDA, and iron, while increasing GSH levels. Additionally, sappanone A increased the protein expression of SLC7A11 and GPX4. Administration of ferroptosis activator reversed the inhibitory effects of sappanone A on IL-1ß-induced inflammation and ECM degradation. More importantly, Sappanone A activated the Nrf2 signaling by targeting SIRT1. The inhibition of sappanone A on ferroptosis was greatly eliminated due to the addition of SIRT1 inhibitor. Furthermore, intra-articular injection of sappanone A mitigated cartilage destruction and ferroptosis in DMM-induced OA rats. In conclusion, sappanone A protects against inflammation and ECM degradation in OA via decreasing chondrocyte ferroptosis by activating the SIRT1/Nrf2 signaling. These findings deepen our understanding of chondrocyte ferroptosis in OA and highlight the therapeutic potential of sappanone A for OA.

Sappanone A Alleviated IL-1ß-Induced Inflammation in OA Chondrocytes through Modulating the NF-κB and Nrf2/HO-1 Pathways.

Objective: This study was to examine the anti-inflammatory effect of sappanone A on interleukin- (IL-) 1ß-stimulated osteoarthritis (OA) chondrocytes. Methods: Chondrocytes were pretreated with sappanone A for 2 h before subsequent IL-1ß stimulation. The mRNA expression levels of iNOs, COX-2, aggrecan, and collagen-II were measured with qRT-PCR. The levels of TNF-α, IL-6, IL-8, MMP-3, and MMP-13 were determined by ELISA. The protein levels of iNOs, COX-2, ADAMTS-4, ADAMTS-5, aggrecan, collagen-II, p-p65, p65, IκBα, Nrf2, and HO-1 were assessed by Western blot. Results: Sappanone A inhibited the IL-1ß-stimulated production of NO, PGE2, iNOS, COX-2, TNF-α, IL-6, and IL-8 in OA chondrocytes. In addition, sappanone A suppressed the expression of MMP-3, MMP-13, ADAMTS-4, and ADAMTS-5 in IL-1ß-stimulated OA chondrocytes. The degradation of ECM components was reversed by sappanone A. Sappanone A prevented NF-κB activation while enhanced Nrf2/HO-1 activation in IL-1ß-treated chondrocytes. Conclusion: Sappanone A may be a potent therapeutic agent for OA.