IL-22 promotes osteoclastogenesis in rheumatoid arthritis through induction of RANKL from synovial fibroblasts (117.25)

Abstract

Abstract This study aims to determine the regulatory role of interleukin(IL)-22 on the expression of receptor activator of NF-kB ligand(RANKL) and the induction of osteoclastogenesis in rheumatoid arthritis(RA). The concentrations of IL-22 and RANKL in sera and synovial fluids(SF)of RA patients were measured by ELISA. After RA synovial fibroblasts were treated with rhIL-22, the expression of RANKL mRNA and protein was determined using real-time PCR,western blot,and immunostaining.Human monocytes were cocultured with IL-22-prestimulated RA synovial fibroblasts and monocyte-colony stimulating factor(M-CSF), and then osteoclastogenesis was determined by counting of TRAP-positive multinucleated cells. Serum and SF IL-22 concentration in RA patients was higher than in osteoarthritis patients and healthy subjects. When RA synovial fibroblasts were treated with rhIL-22, the expression of RANKL mRNA and protein was upregulated in a dose-dependent manner. The IL-22-induced RANKL expression was significantly down-regulated by inhibition of p38 MAPK/NF-kB and JAK-2/STAT3. When human monocytes were cultured with IL-22-prestimulated RA synovial fibroblasts in the absence of RANKL, the monocytes were differentiated into osteoclasts, which was blocked by the inhibition of p38 MAPK/NF-kB and JAK-2/STAT3.Our results suggest that IL-22 up-reugulates RANKL expression in RA synovial fibroblasts and it also promotes osteoclastogenesis, which are mediated by p38 MAPK/NF-kB and JAK-2/STAT3 pathways.