Mahoney David J, Swales Catherine, Athanasou Nicholas A, Bombardieri Michele, Pitzalis Costantino, Kliskey Karolina, Sharif Mohammed, Day Anthony J, Milner Caroline M, Sabokbar Afsie
University of Oxford, Oxford, UK.
Arthritis Rheum. 2011 Apr;63(4):1034-43. doi: 10.1002/art.30201.
TSG-6 (the product of tumor necrosis factor [TNF]-stimulated gene 6) has a potent inhibitory effect on RANKL-mediated bone erosion. The aim of this study was to compare the activity of TSG-6 with that of osteoprotegerin (OPG) and to investigate its role as an autocrine modulator of cytokine-mediated osteoclast formation/activation. We also determined TSG-6 expression in inflammatory joint disease.
The effects of TSG-6, OPG, and the inflammation mediators TNFα, interleukin-1 (IL-1), and IL-6 on the formation of osteoclasts from peripheral blood mononuclear cells and synovial fluid (SF) macrophages were determined by tartrate-resistant acid phosphatase staining. Lacunar resorption and filamentous actin ring formation were measured as indicators of osteoclast activity. The amount of TSG-6 in culture media or SF was quantified by enzyme-linked immunosorbent assay, and expression of TSG-6 in synovial tissue was assessed by immunohistochemistry.
TSG-6 acted in synergy with OPG to inhibit RANKL-mediated bone resorption and was produced by osteoclast precursors and mature osteoclasts in response to TNFα, IL-1, and IL-6. Expression of TSG-6 correlated with inhibition of lacunar resorption; this effect was ameliorated by an anti-TSG-6 antibody. The level of TSG-6 protein was determined in SF from patients with various arthritides; it was highest in patients with inflammatory conditions such as rheumatoid arthritis, in which it correlated with the amount of TSG-6 immunostaining in the synovium. TSG-6 inhibited the activation but not the formation of osteoclasts from SF macrophages.
In the presence of inflammatory cytokines, osteoclasts produced TSG-6 at concentrations that are sufficient to inhibit lacunar resorption. This may represent an autocrine mechanism to limit the degree of bone erosion during joint inflammation.
肿瘤坏死因子（TNF）刺激基因6产物（TSG-6）对核因子κB受体活化因子配体（RANKL）介导的骨侵蚀具有强大的抑制作用。本研究旨在比较TSG-6与骨保护素（OPG）的活性，并研究其作为细胞因子介导的破骨细胞形成/活化的自分泌调节剂的作用。我们还测定了炎症性关节疾病中TSG-6的表达。
通过抗酒石酸酸性磷酸酶染色，测定TSG-6、OPG以及炎症介质TNFα、白细胞介素-1（IL-1）和IL-6对来自外周血单核细胞和滑液（SF）巨噬细胞的破骨细胞形成的影响。测量陷窝吸收和丝状肌动蛋白环形成作为破骨细胞活性的指标。通过酶联免疫吸附测定法定量培养基或SF中TSG-6的量，并通过免疫组织化学评估滑膜组织中TSG-6的表达。
TSG-6与OPG协同作用以抑制RANKL介导的骨吸收，并且破骨细胞前体和成熟破骨细胞在TNFα、IL-1和IL-6刺激下产生TSG-6。TSG-6的表达与陷窝吸收的抑制相关；抗TSG-6抗体可改善这种作用。测定了各种关节炎患者SF中TSG-6蛋白的水平；在类风湿关节炎等炎症性疾病患者中最高，其中它与滑膜中TSG-6免疫染色量相关。TSG-6抑制SF巨噬细胞来源的破骨细胞的活化，但不抑制其形成。
在炎性细胞因子存在的情况下，破骨细胞产生的TSG-6浓度足以抑制陷窝吸收。这可能代表一种自分泌机制，以限制关节炎症期间的骨侵蚀程度。
