期刊
ARTHRITIS AND RHEUMATISM
卷 64, 期 4, 页码 1015-1023出版社
WILEY-BLACKWELL
DOI: 10.1002/art.33446
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资金
- Ministry for Health, Welfare, and Family Affairs, Republic of Korea [A092258]
- Ministry of Education, Science, and Technology, Republic of Korea (National Research Foundation of Korea) [NRF-2010-R1A4A007-0024198]
- Konkuk University School of Medicine
Objective. To examine the regulatory role of interleukin-22 (IL-22) in the expression of RANKL and induction of osteoclastogenesis in rheumatoid arthritis (RA). Methods. 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). Results. 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-kappa B 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-kappa B or JAK-2/STAT-3 signaling was inhibited. Conclusion. 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-kappa B and JAK-2/STAT-3 signaling pathways.
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