The pro-inflammatory effect of NR4A3 in osteoarthritis

NR4A3 is a member of nuclear receptor subfamily 4, which is an important regulator of cellular function and inflammation. In this study, high expression of NR4A3 in human osteoarthritis (OA) cartilage was firstly observed. To explore the relationship between NR4A3 and OA, we used a lentivirus overexpression system to simulate its high expression and study its role in OA. Additionally, siRNA-mediated knockdown of NR4A3 was used to confirm the findings of overexpression experiments. The results showed the stimulatory effect of IL-1β on cartilage matrix-degrading enzyme expression such as MMP-3, 9, INOS and COX-2 was enhanced in NR4A3-overexpressed chondrocytes and decreased in NR4A3-knockdown chondrocytes at both mRNA and protein levels, while IL-1β-induced chondrocyte-specific gene (collagen 2 and SOX-9) degradation was only regulated by NR4A3 at protein level. Furthermore, overexpression of NR4A3 would also enhance EBSS-induced chondrocytes apoptosis, while knockdown of NR4A3 decreased apoptotic level after EBSS treatment. A pathway study indicated that IL-1β-induced NF-κB activation was enhanced by NR4A3 overexpression and reduced by NR4A3 knockdown. We suggest that NR4A3 plays a pro-inflammatory role in the development of OA, and we also speculate that NR4A3 mainly regulates cartilage matrix-degrading gene expression under inflammatory conditions via the NF-κB pathway.