title: IL-15 promotes osteoclastogenesis via the PLD pathway in rheumatoid arthritis.
abstract: 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.
authors.affiliation: The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Mi Kyung
authors.initials: MK
authors.lastname: Park
authors.forename: Yang-Mi
authors.initials: YM
authors.lastname: Her
authors.forename: Mi La
authors.initials: ML
authors.lastname: Cho
authors.forename: Hye-Joa
authors.initials: HJ
authors.lastname: Oh
authors.forename: Eun-Mi
authors.initials: EM
authors.lastname: Park
authors.forename: Seung-Ki
authors.initials: SK
authors.lastname: Kwok
authors.forename: Ji Hyeon
authors.initials: JH
authors.lastname: Ju
authors.forename: Kyung Su
authors.initials: KS
authors.lastname: Park
authors.forename: Do-Sik
authors.initials: DS
authors.lastname: Min
authors.forename: Ho-Youn
authors.initials: HY
authors.lastname: Kim
authors.forename: Sung-Hwan
authors.initials: SH
authors.lastname: Park
mesh_terms: D001172:Arthritis, Rheumatoid / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D019409:Interleukin-15 / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism*; D010712:Phosphatidic Acids / Q000494:pharmacology; D010739:Phospholipase D / Q000235:genetics / Q000378:metabolism*; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013582:Synovial Fluid / Q000737:chemistry; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology
chemical_list: D019409:Interleukin-15; D016328:NF-kappa B; D010712:Phosphatidic Acids; D053245:RANK Ligand; D020928:Mitogen-Activated Protein Kinases; D010739:Phospholipase D; C106801:phospholipase D1