11β-Hydroxysteroid dehydrogenase 1 inhibition attenuates collagen-induced arthritis.
11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) plays an important role in inflammation. However, the role of 11β-HSD1 in rheumatoid arthritis (RA) remains unknown. The purpose of this study was to evaluate the therapeutic effects of a selective 11β-HSD1 inhibitor BVT-2733 in collagen-induced arthritis (CIA) and its underlying mechanisms. CIA mice were treated with BVT-2733 (100 mg/kg, orally) or vehicle twice daily for 2 weeks. Arthritis score and joint histology were investigated. The levels of pro-inflammatory cytokines as well as anti-type II collagen antibody (anti-CII) were detected by ELISA. Western blot analysis was used to assess the activation of NF-κB and NLRP1 inflammasome in joint tissues and in human RA synovial cells. BVT-2733 treatment attenuated the arthritis severity and anti-CII level in CIA mice. BVT-2733 also decreased the levels of serum TNF-α, IL-1β, IL-6 and IL-17. BVT-2733 treatment also significantly reduced synovial inflammation and joint destruction. NF-κB activation and NLRP1 inflammasome assembly were also inhibited in arthritic joints and human RA synovial cells. In conclusion, BVT-2733 exhibits an anti-inflammatory effect on CIA. This protective effect is, at least partly, mediated by inhibition of the NF-κB and NLRP1 inflammasome signaling pathways. 11β-HSD1 inhibition may represent a potential therapeutic target for RA patients.
Department of Nephrology, The General Hospital of Jinan Military Command, Jinan, China.
Lei
L
Zhang
Yubo
Y
Dong
Fangpeng
F
Zou
Min
M
Wu
Changchun
C
Fan
Yaohai
Y
Ding
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors*; D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D001169:Arthritis, Experimental / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001172:Arthritis, Rheumatoid; D002478:Cells, Cultured; D016207:Cytokines / Q000097:blood; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D033023:Foot Joints / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D011859:Radiography; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D013583:Synovial Membrane / Q000166:cytology; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use*; D000096926:Benzenesulfonamides
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D016207:Cytokines; D004791:Enzyme Inhibitors; D007074:Immunoglobulin G; D016328:NF-kappa B; D010879:Piperazines; D013449:Sulfonamides; D013844:Thiazoles; C474501:3-chloro-2-methyl-N-(4-(2-(4-methyl-1-piperazinyl)-2-oxoethyl)-1,3-thiazol-2-yl)benzenesulfonamide; D000096926:Benzenesulfonamides; C529636:NALP1 protein, mouse
11β-Hydroxysteroid dehydrogenase 1; BVT-2733; NF-κB; NLRP1 inflammasome; Rheumatoid arthritis