Abstract
Nrf2 is a critical regulator of the antioxidant defense systems in cellular protection. Emerging evidence has shown that four-octyl itaconate (OI) activates Nrf2 cascade. In this study, the chondroprotective effects of OI on H2O2-stimulated chondrocytes and DMM-induced osteoarthritis (OA) progression were investigated. In primary murine chondrocytes, OI interrupted the binding of Keap1 and Nrf2, leading to accumulation and nuclear translocation of Nrf2 protein, as well as transcription and expression of Nrf2-dependent genes, such as HO-1, NQO1, and GCLC. Furthermore, OI inhibited cell death and apoptosis, as well as H2O2-stimulated ROS generation, lipid peroxidation, superoxide accumulation, and mitochondrial depolarization in chondrocytes, which were abolished by the silence or depletion of Nrf2. In addition, in vivo experiments revealed the therapeutic effects of OI on OA progression in a DMM mouse model. Collectively, these results suggested that OI might serve as a potential treatment for OA progression.
Highlights
Osteoarthritis (OA), featured by progressive cartilage degradation, is one of the most prevailing degenerative joint disorders among the elderly, leading to severe pain and joint dysfunction [1, 2]
The results of coimmunoprecipitation assays (Figures 1(b) and 1(c)) revealed that Kelch-like ECH-associated protein 1 (Keap1) immunoprecipitated with Nuclear factor E2-related factor 2 (Nrf2), and the connection between Keap1 and Nrf2 was disrupted by octyl itaconate (OI), with the concentration of 25 μM based on previous researches [17, 18]
The results demonstrated that Nrf2 translocated into the nucleus, evidenced by the potently elevated Nrf2 protein levels in the nuclei determined by western blotting analysis (Figure 1(d))
Summary
Osteoarthritis (OA), featured by progressive cartilage degradation, is one of the most prevailing degenerative joint disorders among the elderly, leading to severe pain and joint dysfunction [1, 2]. Studies have shown that oxidative stress caused by sustained reactive oxygen species (ROS) production is the major reason for chondrocyte apoptosis, eventually leading to OA pathogenesis [3]. Clearance of ROS offers significant chondrocyte protection against oxidative injury. Nuclear factor E2-related factor 2 (Nrf2) is a principal mediator of the antioxidant defense systems in cellular protection [4,5,6,7]. Keap is modified, leading to separation of Nrf from Keap, as well as Nrf stabilization, accumulation, and translocation into the nucleus. Nrf associates with antioxidant response elements (AREs) and triggers the transcription and expression of a series of Nrf2-dependent genes [10, 11], including heme oxygenase 1 (HO1), NAD (P) H quinone oxidoreductase-1 (NQO1), and γ-glutamyl cysteine ligase catalytic subunit (GCLC), and all of them exhibit robust antioxidant effects to protect cells [5, 12]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
