The protective role of glucocerebrosidase/ceramide in rheumatoid arthritis.

OBJECTIVE: To clarify the role of glucocerebrosidase (GBA) and Ceramide (Cer) in rheumatoid arthritis (RA).

METHODS: GBA-expressing lentivirus were constructed and injected into collagen-induced arthritis (CIA) mice, and compared with CIA mice injected with empty vector. The severity of arthritis and inflammatory mediators were evaluated. Fibroblast-like synoviocytes (FLS) from RA patients were transfected with GBA-expressing lentivirus, or pretreated with C6-Cer. The migration and invasion of FLS, the production of inflammatory cytokines, and the relevant signaling pathways were assessed.

RESULTS: In CIA mice, GBA markedly improved arthritis compared to that in the CIA mice, with increased content of proteoglycan and integral cartilage surfaces and tidemarks. The circulating inflammatory mediators, including interleukin (IL)-1β, IL-6, IL-18, and matrix metalloproteinase (MMP)-1, were significantly reduced in CIA mice with GBA overexpression compared to those in CIA mice. GBA and C6-Cer treatment inhibited migration and invasion of FLS, and suppressed production of inflammatory cytokines and activation of the MAPK pathways.

CONCLUSION: GBA/Cer exhibited a protective role in CIA mice and RA FLS. These results highlight the potential of targeting GBA/Cer as a therapeutic strategy in RA and warrant further investigation.