ZNRF3 Regulates Collagen-Induced Arthritis Through NF-kB and Wnt Pathways.

Although the E3 ubiquitin ligase Zinc and ring finger 3 (ZNRF3) negatively regulates the Wnt signaling pathway, its function in rheumatoid arthritis (RA) is elusive. Here, the effects and the mechanism of ZNRF3 on a mouse model of collagen-induced arthritis (CIA) and human fibroblast-like synoviocytes (FLS) obtained from RA patients were determined. Our results showed that ZNRF3 was highly expressed in tissues and FLSs compared to trauma patients. Lentivirus-mediated silencing of ZNRF3 induced apoptosis decreased cell viability and significantly attenuated inflammation in RA-FLSs via tumor necrosis-α (TNF-α). Additionally, silencing of ZNRF3 reduced knee joint damage and also decreased the level of TNF-α, IL-1ß, and IL-6 in the CIA mouse model. These effects were mediated by the crosstalk between Wnt and NF-κB pathways in RA-FLS.

Diallyl Trisulfide can induce fibroblast-like synovial apoptosis and has a therapeutic effect on collagen-induced arthritis in mice via blocking NF-κB and Wnt pathways.

BACKGROUND: Diallyl Trisulfide (DATS) is an organosulfur compound extracted from garlic bulb, and exerts cardioprotective, anti-inflammatory, antioxidant, antimicrobial and anticancer effects. But its role in the pathogenesis of rheumatoid arthritis (RA) is unknown. Here we explored the influence of DATS on human fibroblast-like synoviocytes (FLS) isolated from RA patients and a mouse model of collagen-induced arthritis (CIA) and the underlying mechanism. METHODS: RA-FLS were cultured and treated with different concentrations of DATS. The CCK8 assay was used to assess cell proliferation while cell apoptosis was detected by flow cytometry and western blot. The IL-8, IL-6 and IL-1ß levels were determined using RT-qPCR and ELISA assay. The expression of proteins of the NF-κB and Wnt pathways were measured using western blot. Furthermore, the effect of DATS was also explored in vivo using the collagen-induced arthritis mouse model. The Th17/Treg pattern obtain from cells of spleen of collagen-induced arthritis mouse model was detected by flow cytometry. RESULTS: Our results showed that DATS could decrease cell viability and introduce apoptosis in RA-FLS. Furthermore, DATS significantly attenuated the production of key inflammatory cytokines induced by RA-FLS cells following treatment with tumor necrosis α (TNF-α) at a concentration of 100 µM or higher. This was due to its inhibitory effect on the NF-κB and Wnt pathway signaling in RA-FLS. Additionally, DATS decreased the production of inflammatory cytokines and regulated the immune function by restoring the balance between Th17 and Treg in CIA mouse model. CONCLUSIONS: In conclusion, DATS may serve as a potential curative agent for RA.