LIGHT (TNFSF14), a novel mediator of bone resorption, is elevated in rheumatoid arthritis
LIGHT (TNFSF14), a novel mediator of bone resorption, is elevated in rheumatoid arthritis
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DOI：
10.1002/art.21821
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发表时间：
2006-05-01
影响因子：
--
通讯作者：
Sabokbar, A.
中科院分区：
文献类型：
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作者：
Edwards, J. R.;Sun, S. G.;Sabokbar, A.
Objective.单核吞噬细胞前体的人破骨细胞形成涉及肿瘤坏死因子（TNF）配体超家族成员及其受体之间的相互作用。LIGHT是一种从活化T细胞表面表达和脱落的跨膜蛋白。由于活化的T细胞与类风湿关节炎（RA）中的破骨细胞生成有关，本研究试图确定LIGHT是否可以调节RAN KL/精氨酸诱导的破骨细胞形成，以确定LIGHT影响破骨细胞生成的机制，并研究RA患者血清中LIGHT的存在。在存在和不存在已知破骨细胞生成因子的中和试剂的情况下，评估LIGHT对人和小鼠破骨细胞形成的影响。采用酶联免疫吸附法检测RA患者血清LIGHT水平。在存在和不存在RANKL的情况下，LIGHT以剂量依赖性方式诱导人外周血单核细胞和小鼠巨噬细胞前体细胞形成破骨细胞，而通过添加骨保护素、RANK：Fc、TNF α或白细胞介素-8或通过阻断LIGHT受体的疱疹病毒进入介质或α-光毒素β受体未观察到抑制作用。然而，破骨细胞的形成显着下降的可溶性诱饵受体的光，DcR 3，并通过阻断抗体的TNF受体的p75组分。RA患者血清LIGHT水平较正常对照组明显升高。我们的研究结果表明，LIGHT促进RANKL介导的破骨细胞生成，它可以诱导破骨细胞形成的机制独立于RANKL。RA患者中LIGHT浓度的增加了LIGHT可能在与局部或全身性骨质流失相关的免疫病理性疾病中发挥作用的可能性。
Objective. Human osteoclast formation from mononuclear phagocyte precursors involves interactions between tumor necrosis factor (TNF) ligand superfamily members and their receptors. LIGHT is a transmembrane protein expressed and shed from the surface of activated T cells. Since activated T cells have been implicated in osteoclastogenesis in rheumatoid arthritis (RA), this study sought to determine whether LIGHT can regulate RAN KL/cytokine-induced osteoclast formation, to identify the mechanism by which LIGHT influences osteoclastogenesis, and to investigate the presence of LIGHT in the serum of RA patients.Methods. The effect of LIGHT on human and murine osteoclast formation was assessed in the presence and absence of neutralizing reagents to known osteoclastogenic factors. Serum levels of LIGHT in RA patients were measured by enzyme-linked immunosorbent assay.Results. In the presence and absence of RANKL, LIGHT induced osteoclast formation from both human peripheral blood mononuclear cells and murine macrophage precursors, in a dose-dependent manner, whereas no inhibition was observed by adding osteoprotegerin, RANK:Fc, TNF alpha, or interleukin-8 or by blocking the LIGHT receptor's herpesvirus entry mediator or lymphotoxin beta receptor. However, formation of osteoclasts was significantly decreased by the soluble decoy receptor for LIGHT, DcR3, and by blocking antibodies to the p75 component of the TNF receptor. A significant increase in LIGHT levels in the serum of RA patients compared with normal controls was also noted.Conclusion. Our results indicate that LIGHT promotes RANKL-mediated osteoclastogenesis and that it can induce osteoclast formation by a mechanism independent of RANKL. The increased concentration of LIGHT in patients with RA raises the possibility that LIGHT may play a role in immunopathogenic conditions that are associated with localized or systemic bone loss.