Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea.
Gyeongsang National University School of Medicine, Gyeongnam, Republic of Korea.
Arthritis Rheumatol. 2015 Oct;67(10):2639-50. doi: 10.1002/art.39244.
To investigate the role played by natural killer T (NKT) cells in osteoclastogenesis and their effects on inflammatory bone destruction.
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 colony-stimulating factor and 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 mice with collagen-induced arthritis.
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-stimulated NKT cells inhibited osteoclastogenesis mainly via interferon-γ production in a cytokine-dependent manner (not by cell-cell contact) and down-regulated osteoclast-associated genes. Mice treated with αGalCer showed less severe arthritis and reduced bone destruction. Moreover, proinflammatory cytokine expression in arthritic joints was found to be reduced by αGalCer treatment.
This study primarily demonstrates that αGalCer-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 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.
探讨自然杀伤 T（NKT）细胞在破骨细胞生成中的作用及其对炎症性骨破坏的影响。
本研究纳入了 25 例类风湿关节炎（RA）患者和 12 例健康对照者。采用外周血单个核细胞（PBMCs）在巨噬细胞集落刺激因子和 RANKL 的存在下进行体外破骨细胞生成实验。将 PBMCs 在体外与α半乳糖神经酰胺（αGalCer）共培养，通过流式细胞术估计 NKT 细胞的增殖指数。在胶原诱导性关节炎小鼠中，确定αGalCer 刺激的 NKT 细胞对炎症和骨破坏的体内影响。
在健康对照者中，αGalCer 显著抑制体外破骨细胞生成，但在 RA 患者中则无此作用。RA 患者对αGalCer 的 NKT 细胞增殖反应和单核细胞中 STAT-1 磷酸化受损。值得注意的是，αGalCer 刺激的 NKT 细胞通过细胞因子依赖性（而非细胞-细胞接触）方式主要通过产生干扰素-γ抑制破骨细胞生成，并下调破骨细胞相关基因。用αGalCer 处理的小鼠关节炎严重程度降低，骨破坏减少。此外，αGalCer 处理还降低了关节炎关节中促炎细胞因子的表达。
本研究主要表明，αGalCer 刺激的 NKT 细胞对破骨细胞生成具有调节作用，并对炎症性骨破坏具有保护作用。然而，也表明在 RA 患者中，αGalCer 的这些作用减弱，且与 NKT 细胞功能障碍有关。这些发现为寻找预防 RA 中骨破坏的新治疗策略提供了重要信息。
