Extracellular high mobility group box chromosomal protein 1 is a coupling factor for hypoxia and inflammation in arthritis
Extracellular high mobility group box chromosomal protein 1 is a coupling factor for hypoxia and inflammation in arthritis
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DOI：
10.1002/art.23729
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发表时间：
2008-09-01
影响因子：
--
通讯作者：
Abeyama, Kazuhiro
中科院分区：
文献类型：
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作者：
Hamada, Takashi;Torikai, Motofumi;Abeyama, Kazuhiro
客观的。组织缺氧与关节炎的发病机制密切相关，受损细胞释放的细胞外高迁移率族盒染色体蛋白1（HMGB-1）也在关节炎的发展中发挥作用。因此，本研究旨在调查细胞外 HMGB-1 可能是关节炎缺氧和炎症之间的耦合因素的假设。方法。测量了炎症性关节病（类风湿性关节炎和假性痛风）患者和非炎症性关节病（骨关节炎）患者滑液（SF）样本中肿瘤坏死因子 a、白介素-6、血管内皮生长因子、乳酸、乳酸脱氢酶和 HMGB-1 的浓度。还在胶原诱导的关节炎 (CIA) 动物模型中检查了组织缺氧和 HMGB-1 的定位。在基于细胞的实验中，研究了缺氧对 HMGB-1 释放及其相关细胞事件（即蛋白质分布和细胞活力）的影响。结果。在来自 HMGB-1 相关炎症性关节病患者的 SF 样本中（即，HMGB-I 水平比非炎症性关节病患者样本的平均水平高出 >2 个标准差的样本）中，HMGB-1 的浓度与组织缺氧标志物乳酸的浓度显着相关。在 HMGB-1 中和可减弱病理表型的 CIA 模型中，还观察到 HMGB-1 与关节炎病变组织缺氧的共定位。在基于细胞的实验中，缺氧通过细胞分泌过程和/或凋亡相关释放诱导细胞外HMGB-1水平显着增加，这比氧化应激增强的坏死细胞损伤中的蛋白质释放更为显着。结论。这些发现表明组织缺氧及其产生的细胞外 HMGB-I 可能在关节炎的发展中发挥重要作用。
Objective. Tissue hypoxia is closely associated with arthritis pathogenesis, and extracellular high mobility group box chromosomal protein 1 (HMGB-1) released from injured cells also has a role in arthritis development. This study was thus undertaken to investigate the hypothesis that extracellular HMGB-1 may be a coupling factor between hypoxia and inflammation in arthritis.Methods. Concentrations of tumor necrosis factor a, interleukin-6, vascular endothelial growth factor, lactic acid, lactate dehydrogenase, and HMGB-1 were measured in synovial fluid (SF) samples from patients with inflammatory arthropathy (rheumatoid arthritis and pseudogout) and patients with noninflammatory arthropathy (osteoarthritis). The localization of tissue hypoxia and HMGB-1 was also examined in animal models of collagen-induced arthritis (CIA). In cell-based experiments, the effects of hypoxia on HMGB-1 release and its associated cellular events (i.e., protein distribution and cell viability) were studied.Results. In SF samples from patients with HMGB-1-associated inflammatory arthropathy (i.e., samples with HMGB-I levels >2 SD above the mean level in samples from patients with noninflammatory arthropathy), concentrations of HMGB-1 were significantly correlated with those of lactic acid, a marker of tissue hypoxia. In CIA models in which the pathologic phenotype could be attenuated by HMGB-1 neutralization, colocalization of HMGB-1 with tissue hypoxia in arthritis lesions was also observed. In cell-based experiments, hypoxia induced significantly increased levels of extracellular HMGB-l by the cellular processes of secretion and/or apoptosis-associated release, which was much more prominent than the protein release in necrotic cell injury potentiated by oxidative stress.Conclusion. These findings indicate that tissue hypoxia and its resultant extracellular HMGB-I might play an important role in the development of arthritis.