Osteoclastogenesis plays an important role in joint destruction in rheumatoid arthritis (RA). IL-15 is a pleiotropic proinflammatory cytokine that appears to help mediate the pathological bone loss. This study was undertaken to explore the signaling molecules essential for osteoclastogenesis mediated by IL-15 in rheumatoid synovial fibroblasts. Expression of phospholipase D1 (PLD1) and osteoclast-related gene expression in synovial tissues and their modulation by treatment with IL-15 and different inhibitors in synovial fibroblasts of RA patients were evaluated using immunohistochemistry and quantitative polymerase chain reaction. The levels of IL-15 in serum and synovial fluid were measured by ELISA. The effects of IL-15 and phosphatidic acid (PA) on osteoclast formation were evaluated in cocultures of rheumatoid synovial fibroblasts and peripheral blood monocytes or monocytes alone in the presence of M-CSF and RANKL. The levels of RANKL and PLD1 but not PLD2 were upregulated significantly by IL-15, and the RANKL level was significantly upregulated by PA in rheumatoid synovial fibroblasts. Blocking PA production with 1-butanol and siRNA against PLD1 significantly inhibited the IL-15-stimulated expression of RANKL and PLD1. IL-15 levels were significantly higher in serum and synovial fluid from patients with RA than in osteoarthritis patients and healthy controls. IL-15 and PA induced osteoclast formation through the mitogen-activated protein kinases (MAPKs) and NF-κB signaling pathways. Activation of PLD1 contributes to IL-15-mediated osteoclastogenesis via the MAPKs and NF-κB signaling pathways in rheumatoid synovial fibroblasts. Our data suggest that PLD1 might be an efficient therapeutic strategy for preventing bone destruction in rheumatoid arthritis.
Bibliographical noteFunding Information:
This research was supported by a grant of the Korea Health Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (grant number A09225 8).
All Science Journal Classification (ASJC) codes
- Immunology and Allergy