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


CONCLUSIONS
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.
Catholic University of Korea, Seoul, Republic of Korea.
Kyoung-Woon
KW
Kim
Hae-Rim
HR
Kim
Jin-Young
JY
Park
Jin-Sil
JS
Park
Hye-Jwa
HJ
Oh
Yun-Ju
YJ
Woo
Mi-Kyung
MK
Park
Mi-La
ML
Cho
Sang-Heon
SH
Lee
D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D002454:Cell Differentiation; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D007378:Interleukins / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010010:Osteoclasts / Q000502:physiology*; D053245:RANK Ligand / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013582:Synovial Fluid / Q000378:metabolism*; D013583:Synovial Membrane / Q000378:metabolism*; D015854:Up-Regulation; D000097043:Interleukin-22
D007378:Interleukins; D053245:RANK Ligand; D000097043:Interleukin-22