Jin HM, Kee SJ, Cho YN, Kang JH, Kim MJ, Jung HJ, Park KJ, Kim TJ, Lee SI, Choi H, Koh JT, Kim N, Park YW. Dysregulated osteoclastogenesis is related to natural killer T cell dysfunction in rheumatoid arthritis. Arthritis Rheumatol. 2015 Jun 19. doi: 10.1002/art.39244. [Epub ahead of print]
OBJECTIVE:
To investigate the role played by NKT cells in osteoclastogenesis and their effects on inflammatory bone destruction.
METHODS:
Patients with RA (n=25) and healthy controls (n=12) were enrolled in this study. In vitro osteoclastogenesis experiments were performed using peripheral blood mononuclear cells (PBMCs) in the presence of M-CSF and receptor activator of nuclear factor κB ligand (RANKL). PBMCs were cultured in vitro with α-galactosylceramide (αGalCer), and proliferation indices of NKT cells were estimated by flow cytometry. In vivo effects of αGalCer-stimulated NKT cells on inflammation and bone destruction were determined in collagen-induced arthritis (CIA) mice.
RESULTS:
In vitro osteoclastogenesis was found to be significantly inhibited by αGalCer in healthy controls, but not in RA patients. Proliferative responses of NKT cells and STAT-1 phosphorylation in monocytes in response to αGalCer were impaired in RA patients. Notably, αGalCer-stimulatedNKT cells inhibited osteoclastogenesis mainly via interferon-γ production, in a cytokine-dependent manner (not by cell-cell contact), and down-regulated osteoclast-associated genes. αGalCer-treated mice showed less severe arthritis and reduced bone destruction. Moreover, proinflammatory cytokine expression in arthritic joints was found to be reduced by αGalCer treatment.
CONCLUSIONS:
This study primarily demonstrates that αGalCer-stimulated NKT cells have a regulatory effect on osteoclastogenesis and a protective effect on inflammatory bone destruction. However, it also shows that these effects of αGalCer are diminished in RA patients, and that this is related to NKT cell dysfunction. These findings provide important information for those searching for novel therapeutic strategies to prevent bone destruction in RA. This article is protected by copyright. All rights reserved.
OBJECTIVE:
To investigate the role played by NKT cells in osteoclastogenesis and their effects on inflammatory bone destruction.
METHODS:
Patients with RA (n=25) and healthy controls (n=12) were enrolled in this study. In vitro osteoclastogenesis experiments were performed using peripheral blood mononuclear cells (PBMCs) in the presence of M-CSF and receptor activator of nuclear factor κB ligand (RANKL). PBMCs were cultured in vitro with α-galactosylceramide (αGalCer), and proliferation indices of NKT cells were estimated by flow cytometry. In vivo effects of αGalCer-stimulated NKT cells on inflammation and bone destruction were determined in collagen-induced arthritis (CIA) mice.
RESULTS:
In vitro osteoclastogenesis was found to be significantly inhibited by αGalCer in healthy controls, but not in RA patients. Proliferative responses of NKT cells and STAT-1 phosphorylation in monocytes in response to αGalCer were impaired in RA patients. Notably, αGalCer-stimulatedNKT cells inhibited osteoclastogenesis mainly via interferon-γ production, in a cytokine-dependent manner (not by cell-cell contact), and down-regulated osteoclast-associated genes. αGalCer-treated mice showed less severe arthritis and reduced bone destruction. Moreover, proinflammatory cytokine expression in arthritic joints was found to be reduced by αGalCer treatment.
CONCLUSIONS:
This study primarily demonstrates that αGalCer-stimulated NKT cells have a regulatory effect on osteoclastogenesis and a protective effect on inflammatory bone destruction. However, it also shows that these effects of αGalCer are diminished in RA patients, and that this is related to NKT cell dysfunction. These findings provide important information for those searching for novel therapeutic strategies to prevent bone destruction in RA. This article is protected by copyright. All rights reserved.
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