Tenosynovitis and osteoclast formation as the initial preclinical changes in a murine model of inflammatory arthritis
Tenosynovitis and osteoclast formation as the initial preclinical changes in a murine model of inflammatory arthritis
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DOI：
10.1002/art.22313
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发表时间：
2007-01-01
影响因子：
--
通讯作者：
Schett, Georg
中科院分区：
文献类型：
--
作者：
Hayer, Silvia;Redlich, Kurt;Schett, Georg
目标。目的：明确临床明显关节炎发病前、发病时及发病后不久关节炎症初始变化的性质。对人类肿瘤坏死因子转基因小鼠在关节炎临床前期、发病初期和临床早期的临床、组织学、免疫表型、血清学和分子水平的变化进行了评估。此外，在这些疾病的初始阶段，研究了遗传性破骨细胞缺陷和对肿瘤坏死因子的药物抑制的影响。甚至在临床症状开始之前就观察到了最初的关节改变。第一个病理事件是肌腱鞘内粒细胞和巨噬细胞的渗透，以及炎症的肌腱鞘旁破骨细胞的形成。腱鞘膜炎迅速导致鞘改建成血管疙瘩样组织，形成破骨细胞，侵入邻近的矿化软骨。早期病变与IL-1和IL-6的上调以及p38MAPK和ERK的激活有关。相反，破骨细胞的缺失导致腱鞘炎脱离对软骨和骨的侵袭。阻断肿瘤坏死因子还可减轻与腱鞘炎相关的病理改变。结构损伤甚至在关节炎的临床症状出现之前就开始了，累及肌腱鞘以及邻近的软骨和骨骼。这些结果表明，腱鞘炎是关节炎的起始特征，关节破坏从疾病开始就开始了。因此，我们的研究结果强调了立即开始对类风湿关节炎患者进行有效治疗的重要性。
Objective. To determine the nature of the initial changes of joint inflammation occurring before, at the time of, and shortly after onset of clinically apparent arthritis.Methods. Human tumor necrosis factor (TNF)-transgenic mice were assessed for clinical, histologic, immunophenotypic, serologic, and molecular changes at the preclinical phase of arthritis, at the onset of disease, and at the stage of early clinical disease. In addition, the effects of a genetic osteoclast deficiency and pharmacologic inhibition of TNF were studied in these initial phases of disease.Results. Initial articular changes were observed even before the start of clinical symptoms. Infiltration of the tendon sheaths by granulocytes and macrophages as well as formation of osteoclasts next to the inflamed tendon sheaths were the first pathologic events. Tenosynovitis rapidly led to remodeling of the sheaths into pannus-like tissue, which formed osteoclasts that invaded the adjacent mineralized cartilage. Early lesions were associated with up-regulation of interleukin-1 (IL-1) and IL-6 as well as activation of p38 MAPK and ERK. In contrast, absence of osteoclasts led to uncoupling of tenosynovitis from invasion into cartilage and bone. TNF blockade also attenuated the pathologic changes associated with tenosynovitis.Conclusion. Structural damage begins even before the onset of clinical symptoms of arthritis and involves the tendon sheaths as well as adjacent cartilage and bone. These results suggest that tenosynovitis is an initiating feature of arthritis and that joint destruction starts right from the onset of disease. Our findings thus underscore the importance of immediate initiation of an effective therapy in patients with rheumatoid arthritis.