Metastasis-inducing S100A4 protein is associated with the disease activity of rheumatoid arthritis
Metastasis-inducing S100A4 protein is associated with the disease activity of rheumatoid arthritis
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DOI：
10.1093/rheumatology/kep316
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发表时间：
2009-12-01
期刊：
影响因子：
5.5
通讯作者：
Senolt, Ladislav
中科院分区：
文献类型：
--
作者：
Oslejskova, Lucie;Grigorian, Mariam;Senolt, Ladislav
目标.评估转移诱导蛋白S100 A4与RA患者疾病活动性之间的相关性，并证实TNF-α阻断治疗对这些患者血浆S100 A4水平的影响。分析了40例未接受过抗TNF-α治疗的活动性RA患者的S100 A4蛋白血浆水平。40例患者中，25例接受阿达木单抗治疗，并随时间进行监测。使用尺寸排阻凝胶色谱法分析S100 A4的构象形式。RT-PCR和ELISA分别检测TNF-α mRNA表达和蛋白合成。RA患者血清S100 A4水平与疾病活动性显著相关（r = 0.41; P < 0.01）。阿达木单抗治疗12周后，S100 A4的构象从多聚体形式明显转变为二聚体形式，而S100 A4蛋白的总水平保持不变。这表明，生物活性（多聚体）S100 A4可能在阿达木单抗成功治疗后下降。此外，我们还发现，与用S100 A4多聚体刺激的单核细胞相比，用S100 A4多聚体刺激的单核细胞的TNF-α mRNA显著上调（P <0.01），并且蛋白质释放到细胞培养基中（P < 0.001）。这是第一项表明S100 A4蛋白水平与RA疾病活动相关的研究。此外，在RA患者中成功的TNF-α阻断治疗后，只有生物活性形式的S100 A4而不是总量减少。这些数据支持S100 A4多聚体在RA发病机制中的重要作用。
Objectives. To evaluate the association between metastasis-inducing protein S100A4 and disease activity in patients with RA, and to demonstrate the effect of TNF-alpha blocking therapy on plasma levels of S100A4 in these patients.Methods. Plasma levels of the S100A4 protein were analysed in 40 anti-TNF-alpha naive patients with active RA. Of the 40 patients, 25 were treated with adalimumab and monitored over time. The conformational form of S100A4 was analysed using size-exclusion gel chromatography. TNF-alpha mRNA expression and protein synthesis were analysed by RT-PCR and ELISA, respectively.Results. Baseline levels of S100A4 were significantly correlated with disease activity in RA patients (r = 0.41; P < 0.01). After 12 weeks of treatment with adalimumab, there was an obvious shift in the conformations of S100A4 from the multimeric to the dimeric forms, whereas the total levels of the S100A4 protein remained unchanged. This suggests that the bioactive (multimer) S100A4 may decline in response to successful treatment with adalimumab. In addition, we showed significant up-regulation of TNF-alpha mRNA (P < 0.01), and protein release to the cell culture medium of monocytes stimulated with the S100A4 multimer compared with those treated with the dimer and to the unstimulated monocytes (P < 0.001).Conclusions. This is the first study to show that the levels of the S100A4 protein are correlated with RA disease activity. Furthermore, only the bioactive form, but not the total amount of S100A4, decreases after successful TNF-alpha blocking therapy in patients with RA. These data support an important role for the S100A4 multimer in the pathogenesis of RA.