Dysregulated Osteoclastogenesis Is Related to Natural Killer T Cell Dysfunction in Rheumatoid Arthritis

Abstract

Objective. To investigate the role played by natural killer T (NKT) cells in osteoclastogenesis and their effects on inflammatory bone destruction. Methods. Patients with rheumatoid arthritis (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 macrophage colonystimulating factor and RANKL. PBMCs were cultured in vitro with alpha-galactosylceramide (alpha GalCer), and proliferation indices of NKT cells were estimated by flow cytometry. In vivo effects of alpha GalCer-stimulated NKT cells on inflammation and bone destruction were determined in mice with collagen-induced arthritis. Results. In vitro osteoclastogenesis was found to be significantly inhibited by alpha GalCer in healthy controls but not in RA patients. Proliferative responses of NKT cells and STAT-1 phosphorylation in monocytes in response to alpha GalCer were impaired in RA patients. Notably, alpha GalCer-stimulated NKT cells inhibited osteoclasto-genesis mainly via interferon-gamma production in a cytokine-dependent manner (not by cell-cell contact) and down-regulated osteoclast-associated genes. Mice treated with alpha GalCer showed less severe arthritis and reduced bone destruction. Moreover, proinflammatory cytokine expression in arthritic joints was found to be reduced by alpha GalCer treatment. Conclusion. This study primarily demonstrates that alpha GalCer-stimulated NKT cells have a regulatory effect on osteoclastogenesis and a protective effect against inflammatory bone destruction. However, it also shows that these effects of alpha GalCer 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.y