MDM2 promotes rheumatoid arthritis via activation of MAPK and NF-κB

• RA-FLS MDM2 expression was positively correlated with disease activity.
• MDM2 knockdown inhibited inflammation in RA-FLS via MAPK and NF-κB.
• Nutlin-3a treatment attenuated the arthritis and inflammation in CIA.
• Nutlin-3a treatment inhibited the proinflammatory cytokines and MMPs in CIA.
• Nutlin-3a treatment inhibited MAPK and NF-κB activation in CIA.

Murine double minute-2 (MDM2) has pleiotropic roles in immune activation and regulation. However, the role of MDM2 in rheumatoid arthritis (RA) remains unknown. We undertook this study to investigate the role of MDM2 in rheumatoid arthritis (RA). Fibroblast-like synoviocytes (FLS) were isolated from 25 patients with active RA and 25 patients with osteoarthritis (OA). FLS were stimulated in the presence or absence of IL-1β in vitro. Mice with collagen-induced arthritis (CIA) were treated with Nutlin-3a (100 mg/kg) or vehicle twice daily for 2 weeks. MDM2 expression was determined by Western blot. MDM2 was down-regulated by specific gene silencing. The concentrations of pro-inflammatory cytokines and matrix metalloproteinases (MMPs) were analyzed using enzyme-linked immunosorbent assay (ELISA). The pathways of mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) were investigated by Western blot. Arthritis scoring and histological analysis were conducted. MDM2 expression was significantly higher in RA-FLS than in OA-FLS. MDM2 protein expression was positively correlated with disease activity of RA. MDM2 promoted the production of TNF-α, IL-6, MMP1 and MMP13 through MAPK and NF-κB pathways in RA-FLS. Nutlin-3a treatment decreased the arthritis severity and joint damage in CIA. Nutlin-3a also inhibited the activation of MAPK and NF-κB in arthritic joints. In conclusion, MDM2 inhibition exhibits anti-inflammatory activity and MDM2 might be a new therapeutic target for RA.