Kwok Seung-Ki, Cho Mi-La, Park Mi-Kyung, Oh Hye-Joa, Park Jin-Sil, Her Yang-Mi, Lee Seon-Yeong, Youn Jeehee, Ju Ji Hyeon, Park Kyung Su, Kim Sung-Il, Kim Ho-Youn, Park Sung-Hwan
Division of Rheumatology, Department of Internal Medicine, School of Medicine, Catholic University of Korea, Seoul, South Korea.
Arthritis Rheum. 2012 Mar;64(3):740-51. doi: 10.1002/art.33390.
Bone destruction is a critical pathology involved in the functional disability caused by rheumatoid arthritis (RA). Osteoclasts, which are specialized bone-resorbing cells regulated by cytokines such as RANKL, are implicated in bone destruction in RA. The aim of this study was to determine whether interleukin-21 (IL-21), a potent immunomodulatory 4-α-helical bundle type 1 cytokine, has osteoclastogenic activity in patients with RA and in mice with collagen-induced arthritis (CIA).
The expression of IL-21 in synovial tissue was examined using immunohistochemistry. The concentrations of IL-21 in serum and synovial fluid were determined by enzyme-linked immunosorbent assay. The levels of RANKL and osteoclastogenic markers were measured using real-time polymerase chain reaction. CD14+ monocytes from patients with RA or mouse bone marrow cells were cocultured with fibroblast-like synoviocytes (FLS) from patients with RA or CD4+ T cells from mice with CIA in the presence of IL-21 and subsequently stained for tartrate-resistant acid phosphatase activity to determine osteoclast formation.
IL-21 was up-regulated in the synovium, synovial fluid, and serum of patients with RA and in the synovium and serum of mice with CIA. IL-21 induced RANKL expression in mixed joint cells and CD4+ T cells from mice with CIA and in CD4+ T cells and FLS from patients with RA. Moreover, IL-21 enhanced in vitro osteoclastogenesis without the presence of RANKL-providing cells and by inducing RANKL expression in CD4+ T cells and FLS.
Our data suggest that IL-21 promotes osteoclastogenesis in RA. We believe that therapeutic strategies targeting IL-21 might be effective for the treatment of patients with RA, especially in preventing bone destruction.
骨破坏是类风湿关节炎（RA）所致功能障碍的关键病理表现。破骨细胞是由细胞因子如RANKL调节的专门负责骨吸收的细胞，与RA中的骨破坏有关。本研究旨在确定白细胞介素-21（IL-21）这一具有强大免疫调节作用的1型4-α-螺旋束细胞因子在RA患者及胶原诱导性关节炎（CIA）小鼠中是否具有破骨细胞生成活性。
采用免疫组织化学法检测滑膜组织中IL-21的表达。通过酶联免疫吸附测定法测定血清和滑液中IL-21的浓度。使用实时聚合酶链反应测量RANKL和破骨细胞生成标志物的水平。将RA患者的CD14+单核细胞或小鼠骨髓细胞与RA患者的成纤维样滑膜细胞（FLS）或CIA小鼠的CD4+ T细胞在IL-21存在的情况下共培养，随后对耐酒石酸酸性磷酸酶活性进行染色以确定破骨细胞形成。
IL-21在RA患者的滑膜、滑液和血清中以及CIA小鼠的滑膜和血清中上调。IL-21在CIA小鼠的混合关节细胞和CD4+ T细胞以及RA患者的CD4+ T细胞和FLS中诱导RANKL表达。此外，IL-21在不存在提供RANKL的细胞的情况下通过诱导CD4+ T细胞和FLS中的RANKL表达增强体外破骨细胞生成。
我们的数据表明IL-21促进RA中的破骨细胞生成。我们认为针对IL-21的治疗策略可能对RA患者的治疗有效，尤其是在预防骨破坏方面。
