Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 185, Issue 11, Pages 3011-3024Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2015.07.017
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Funding
- Research Fund of Seoul St.Mary's Hospital
- Catholic University of Korea
- National Research Foundation of Korea grant
- Korean Government [NRF-2010-0024198, NRF-2013R1A1A1008171, NRF-2014R1A2A2A01007223]
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This study determined the effect of type 17 helper T-cell (Th17) cytokines on osteoclastogenesis in rheumatoid arthritis (RA). The expression of IL-17 and receptor activator of NE-kappa B ligand (RANKL) was determined in synovial tissue, fibroblast-like synoviocytes (FLSs), and synovial fluids of RA patients using immunostaining and enzyme-linked immunosorbent assay. Th17 cytokine induced RANKL expression was studied in RA FLS by using real-time PCR, luciferase activity assays, and Western blot analysis. Human peripheral blood monocytes were cultured with macrophage colony-stimulating factor and Th17 cytokines, after which osteoclastogenesis was evaluated by counting the number of tartrate-resistant acid phosphatase positive multinucleated cells. Osteoclastogenesis was also evaluated after monocytes were co-cultured with IL-17-prestimulated FLS. There was significant correlation between RANKL and IL-17 levels in RA synovial fluid. IL-17, IL-21, and IL-22 increased the expression of Rankl mRNA in RA FLS, and the IL-17 induced RANKL expression decreased by the inhibition of Act1, tumor necrosis factor receptor associated factor 6, NE-kappa B, and activator protein-1. Th17 cytokines and IL-17 prestimulated FLS induced osteoclastogenesis from monocytes in the absence of exogenous RANKL. The osteoclastic effect was reduced by inhibition of tumor necrosis factor-cc. Th17 cytokines have a dual effect on osteoclastogenesis in RA: direct induction of osteoclastogenesis from monocytes and up-regulation of RANKL production in RA FLS. This Th17 cytokine/RANKL axis could be a potential therapeutic target for bone destruction in RA.
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