HMGA1 Aggravates Oxidative Stress Injury and Inflammatory Responses in IL-1β-Induced Primary Chondrocytes through the JMJD3/ZEB1 Axis

Abstract

Introduction: Osteoarthritis (OA) is associated with oxidative stress injury (OSI) and inflammatory responses in chondrocytes. This study sought to explore the mechanism of high mobility group A1 (HMGA1) in interleukin-1beta (IL-1β)-induced OSI and inflammatory responses in primary chondrocytes. Methods: Primary chondrocytes were cultured and treated with IL-1β to establish an OA-cell model. Levels of HMGA1, Jumonji domain-containing 3 (JMJD3), and ZEB1 in cells were determined by real-time quantitative polymerase chain reaction and Western blot analysis. Cell viability, contents of tumor necrosis factor-α, IL-6, and IL-10, reactive oxygen species level, and glutathione peroxidase activity were assessed by the cell counting kit-8 assay, enzyme-linked immunosorbent assay, and assay kits. Enrichment levels of HMGA1 on the JMJD3 promoter and enrichment levels of JMJD3 and trimethylated histone H3 at lysine 27 (H3K27me3) on the ZEB1 promoter region were determined by chromatin immunoprecipitation. Functional rescue experiments were performed to analyze the impact of ZEB1 and JMJD3 on IL-1β-induced chondrocytes. Results: IL-1β treatment induced HMGA1 upregulation, OSI, and inflammatory responses in chondrocytes. HMGA1 downregulation reduced IL-1β-induced OSI and inflammatory responses in chondrocytes. Mechanically, HMGA1 was bound to the JMJD3 promoter to promote JMJD3 transcription, and JMJD3 induced demethylation of H3K27me3 on the ZEB1 promoter to promote ZEB1 transcription. Overexpression of JMJD3 or ZEB1 neutralized the protective role of silencing HMGA1 in IL-1β-induced chondrocytes. Conclusion: HMGA1 aggravated IL-1β-induced OSI and inflammatory responses in chondrocytes through the promotion of JMJD3 and ZEB1.