Th17 cytokines regulate osteoclastogenesis in rheumatoid arthritis.

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.

Kim KW ，Kim HR ，Kim BM ，Cho ML ，Lee SH ... -  《-》

TLR-3 enhances osteoclastogenesis through upregulation of RANKL expression from fibroblast-like synoviocytes in patients with rheumatoid arthritis.

Kim KW ，Cho ML ，Oh HJ ，Kim HR ，Kang CM ，Heo YM ，Lee SH ，Kim HY ... -  《-》

Interleukin-22 promotes osteoclastogenesis in rheumatoid arthritis through induction of RANKL in human synovial fibroblasts.

To examine the regulatory role of interleukin-22 (IL-22) in the expression of RANKL and induction of osteoclastogenesis in rheumatoid arthritis (RA). Concentrations of IL-22 and RANKL in the serum and synovial fluid of RA patients were measured using enzyme-linked immunosorbent assay. RA synovial fibroblasts were treated with recombinant human IL-22 (rhIL-22), and the expression of RANKL messenger RNA (mRNA) and protein was measured using real-time polymerase chain reaction, Western blotting, and intracellular immunostaining. Human monocytes were cocultured with IL-22-prestimulated RA synovial fibroblasts and macrophage colony-stimulating factor, and osteoclastogenesis was assessed by counting the multinucleated cells (those staining positive for tartrate-resistant acid phosphatase). The IL-22 concentration in the synovial fluid was higher in RA patients than in patients with osteoarthritis (OA). The serum IL-22 concentration was also higher in RA patients than in OA patients and healthy volunteers, and this correlated with serum titers of rheumatoid factor and anti-cyclic citrullinated peptide antibodies. In RA synovial fibroblasts treated with rhIL-22, the expression of RANKL mRNA and protein was increased in a dose-dependent manner. IL-22-induced RANKL expression was down-regulated significantly by the inhibition of p38 MAPK/NF-κB or JAK-2/STAT-3 signaling. In human monocytes cocultured with IL-22-prestimulated RA synovial fibroblasts in the absence of exogenous RANKL, the monocytes differentiated into osteoclasts, but this osteoclastogenesis decreased after p38 MAPK/NF-κB or JAK-2/STAT-3 signaling was inhibited. These results show that IL-22 up-regulates RANKL expression in RA synovial fibroblasts and induces osteoclastogenesis. These effects are mediated by the p38 MAPK/NF-κB and JAK-2/STAT-3 signaling pathways.

Kim KW ，Kim HR ，Park JY ，Park JS ，Oh HJ ，Woo YJ ，Park MK ，Cho ML ，Lee SH ... -  《-》

Quercetin, a Plant Polyphenol, Has Potential for the Prevention of Bone Destruction in Rheumatoid Arthritis.

Kim HR ，Kim BM ，Won JY ，Lee KA ，Ko HM ，Kang YS ，Lee SH ，Kim KW ... -  《-》

N-acetyl-l-cysteine controls osteoclastogenesis through regulating Th17 differentiation and RANKL production in rheumatoid arthritis.

Kim HR ，Kim KW ，Kim BM ，Lee KA ，Lee SH ... -  《-》