Interleukin-21 promotes osteoclastogenesis in RAW264.7 cells through the PI3K/AKT signaling pathway independently of RANKL.
Cytokines play a key role in the bone destruction of rheumatoid arthritis (RA). Interleukin-21 (IL-21) promotes osteoclastogenesis in RA in a receptor activator of nuclear factor-κB ligand (RANKL)-dependent way. Whether IL-21 is capable of promoting osteoclastogenesis directly in the absence of RANKL remains unknown. In the present study, we examined the osteoclastogenic activity of IL-21 in RAW264.7 cells in the absence of RANKL. We found that IL-21 enhanced osteoclastogenesis and this was demonstrated by increased numbers of tartrate-resistant acid phosphatase (TRAP)-positive stained, multinucleated cells compared with the negative control. Western blot analysis and immunocytochemistry showed the positive expression of calcitonin receptor (CTR) in the IL-21 group. RT-PCR and RT-qPCR also verified the increased mRNA expression of CTR and cathepsin K in the IL-21 group compared with the negative control. The scanning electronic microscope images showed a few resorption pits on the bone slices cultured with IL-21. The phosphoinositide 3-kinase (PI3K)/AKT pathway inhibitor LY294002 significantly suppressed IL-21-induced osteoclastogenesis. Taken together, these findings suggest that IL-21 has direct osteoclastogenic potential independently of RANKL. IL-21 may promote osteoclastogenesis through the PI3K/AKT signaling pathway. Therapy targeting IL-21 may be of value in preventing bone erosions in patients with RA.
Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing 100191, P.R. China.
Rui
R
Xing
Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing 100191, P.R. China.
Yingjian
Y
Zhang
Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing 100191, P.R. China.
Changhong
C
Li
Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing 100191, P.R. China.
Lin
L
Sun
Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing 100191, P.R. China.
Lin
L
Yang
Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing 100191, P.R. China.
Jinxia
J
Zhao
Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing 100191, P.R. China.
Xiangyuan
X
Liu
D000328:Adult; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000473:pathology; D001862:Bone Resorption / Q000473:pathology; D056657:Cathepsin K / Q000378:metabolism; D005260:Female; D006801:Humans; D007378:Interleukins / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D010012:Osteogenesis / Q000187:drug effects*; D053244:Osteoprotegerin / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D053245:RANK Ligand / Q000378:metabolism*; D000067996:RAW 264.7 Cells; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000378:metabolism; D018003:Receptors, Calcitonin / Q000378:metabolism; D018123:Receptors, Interleukin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D000098546:Interleukin-21
D007378:Interleukins; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018003:Receptors, Calcitonin; D018123:Receptors, Interleukin; C505687:Tnfrsf11a protein, mouse; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D056657:Cathepsin K; D000098546:Interleukin-21