title: Th17 cytokines regulate osteoclastogenesis in rheumatoid arthritis.
abstract: 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 NF-κB 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, NF-κB, 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-α. 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.
authors.affiliation: Conversant Research Consorcium in Immunologic Disease, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Kyoung-Woon
authors.initials: KW
authors.lastname: Kim
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Republic of Korea.
authors.forename: Hae-Rim
authors.initials: HR
authors.lastname: Kim
authors.affiliation: Conversant Research Consorcium in Immunologic Disease, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Bo-Mi
authors.initials: BM
authors.lastname: Kim
authors.affiliation: Conversant Research Consorcium in Immunologic Disease, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; Rheumatism Research Center, The Catholic University of Korea, Seoul, Republic of Korea. Electronic address: iammila@catholic.ac.kr.
authors.forename: Mi-La
authors.initials: ML
authors.lastname: Cho
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Republic of Korea. Electronic address: shlee@kuh.ac.kr.
authors.forename: Sang-Heon
authors.initials: SH
authors.lastname: Lee
mesh_terms: D000135:Acid Phosphatase; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000473:pathology; D002454:Cell Differentiation; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D010010:Osteoclasts / Q000276:immunology / Q000378:metabolism*; D010012:Osteogenesis / Q000276:immunology; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013582:Synovial Fluid / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism; D000071681:Tartrate-Resistant Acid Phosphatase; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D016207:Cytokines; D007527:Isoenzymes; D053245:RANK Ligand; D048029:TNF Receptor-Associated Factor 6; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D016173:Macrophage Colony-Stimulating Factor; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase