Inhibition of glycogen synthase kinase-3β suppresses inflammatory responses in rheumatoid arthritis fibroblast-like synoviocytes and collagen-induced arthritis

• Published in: Joint, bone, spine : revue du rhumatisme bone, spine : revue du rhumatisme, 2014-05, Vol.81 (3), p.240-246
• Main Authors: Kwon, Yong-Jin, Yoon, Chong-Hyeon, Lee, Sang-Won, Park, Yong-Beom, Lee, Soo-Kon, Park, Min-Chan
• Format: Article
• Language: English
• Subjects: Animals; Antirheumatic Agents - metabolism; Antirheumatic Agents - pharmacology; Antirheumatic Agents - therapeutic use; Arthritis, Experimental - drug therapy; Arthritis, Experimental - metabolism; Arthritis, Experimental - pathology; Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - metabolism; Arthritis, Rheumatoid - pathology; Cells, Cultured; Collagen-induced arthritis; Disease Models, Animal; Fibroblast-like synoviocytes; Fibroblasts - drug effects; Glycogen Synthase Kinase 3 - antagonists & inhibitors; Glycogen Synthase Kinase 3 - metabolism; Glycogen synthase kinase-3β; Humans; Inflammation - drug therapy; Inflammation - metabolism; Internal Medicine; Mice; Rheumatoid arthritis; Rheumatology; Synovial Membrane - drug effects; Synovial Membrane - pathology
• ISSN: 1297-319X; 1778-7254
• DOI: 10.1016/j.jbspin.2013.09.006

Abstract Objectives Glycogen synthase kinase (GSK)-3β, a serine/threonine protein kinase, has been implicated as a regulator of the inflammatory response. This study was performed to evaluate the effect of selective GSK-3β inhibitors in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) and collagen-induced arthritis (CIA). Method FLS from RA patients were treated with selective GSK-3β inhibitors, including lithium chloride, 6-bromoindirubin-3′-oxime (BIO), or 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8). The effects of GSK-3β inhibition on pro-inflammatory mediators were determined by real-time PCR and ELISA. The levels of NF-κB, phosphorylated JNK, c-jun, ATF-2 and p-38 proteins were evaluated by western blot analysis. The in vivo effects of GSK-3β inhibitors were examined in mice with CIA. Results Treatment of RA FLS with GSK-3β inhibitors induced dose-dependent reductions in gene expression and the production of pro-inflammatory mediators. The levels of NF-κB, phosphorylated JNK, c-jun, ATF-2 and p-38 were decreased following treatment with GSK-3β inhibitors. GSK-3β inhibitors treatment attenuated clinical and histological severities of CIA in mice. Infiltration of T-cells, macrophages, and tartrate-resistant acid phosphatase positive cells was decreased in joint sections of CIA mice by GSK-3β inhibitors treatment. Serum levels of IL-1β, IL-6, TNF-α and IFN-γ in CIA mice were also significantly decreased in dose-dependent manners by treatment with GSK-3β inhibitors. Conclusion Treatment with GSK-3β inhibitors suppressed inflammatory responses in RA FLS and CIA mice. These findings suggest that the inhibition of GSK-3β can be used as an effective therapeutic agent for RA.