van de Loo F A, Arntz O J, van Enckevort F H, van Lent P L, van den Berg W B
University Hospital Nijmegen, The Netherlands.
Arthritis Rheum. 1998 Apr;41(4):634-46. doi: 10.1002/1529-0131(199804)41:4<634::AID-ART10>3.0.CO;2-1.
To investigate the role of nitric oxide (NO) and interleukin-1 in (IL-1) joint inflammation and cartilage destruction during zymosan-induced gonarthritis (ZIA).
Monarticular arthritis was elicited by intraarticular injection of zymosan. The effect of NO deficiency on arthritis was studied in mice with genetically disrupted NOS2. The role of IL-1 was examined by treating wild-type mice with neutralizing anti-murine IL-1(alpha+beta) antibodies. Joint swelling was measured externally by the increased uptake of circulating 99mtechnetium pertechnetate. Proteoglycan (PG) synthesis was assessed using 35S-sulfate incorporation into patellae ex vivo. Histology evaluated exudation and infiltration of leukocytes and the extent of cartilage destruction.
The proinflammatory mediators NO, IL-1, and IL-6 were released by the articular tissues during the first hours of inflammation. Interestingly, anti-IL-1 treatment moderately reduced, and NOS2 deficiency moderately enhanced, joint swelling. However, the influx of neutrophils into the joint occurred independently of IL-1 and NOS2 activities. In the first week of inflammation, chondrocyte PG synthesis was significantly suppressed and chondrocytes became unresponsive to their essential anabolic factor, insulin-like growth factor 1 (IGF-1). Anti-IL-1 treatment or NOS2 deficiency prevented the inhibition of PG synthesis, and the chondrocytes remained IGF-1 responsive. Intraarticular injections of IL-1alpha into NOS2-deficient mice did not affect PG synthesis, thus proving that NO mediated this IL-1 effect in vivo. Furthermore, histology showed that cartilage PG loss was markedly ameliorated in NOS2-deficient and anti-IL-1-treated mice. Intermediate cartilage pathology was found in mice that were heterozygous for disrupted NOS2.
IL-1 and NO play a minor role in edema and neutrophil influx, but a major role in cartilage destruction of ZIA. In this model of murine arthritis, cartilage destruction was, for the most part, caused by pronounced suppression of PG synthesis and IGF-1 unresponsiveness of the chondrocytes, which were induced by de novo-synthesized IL-1 and were mediated by NOS2 activation.
研究一氧化氮（NO）和白细胞介素-1（IL-1）在酵母聚糖诱导的膝关节炎（ZIA）关节炎症和软骨破坏中的作用。
通过关节内注射酵母聚糖诱发单关节关节炎。在基因敲除NOS2的小鼠中研究NO缺乏对关节炎的影响。通过用中和抗小鼠IL-1（α+β）抗体处理野生型小鼠来研究IL-1的作用。通过循环高锝酸盐摄取增加来外部测量关节肿胀。使用35S-硫酸盐掺入离体髌骨来评估蛋白聚糖（PG）合成。组织学评估白细胞的渗出和浸润以及软骨破坏的程度。
在炎症的最初几个小时内，关节组织释放促炎介质NO、IL-1和IL-6。有趣的是，抗IL-1治疗适度减轻，而NOS2缺乏适度增强关节肿胀。然而，中性粒细胞向关节内的流入独立于IL-1和NOS2活性发生。在炎症的第一周，软骨细胞PG合成被显著抑制，软骨细胞对其必需的合成代谢因子胰岛素样生长因子1（IGF-1）变得无反应。抗IL-1治疗或NOS2缺乏可防止PG合成的抑制，并且软骨细胞保持对IGF-1有反应。向NOS2缺乏的小鼠关节内注射IL-1α不影响PG合成，从而证明NO在体内介导了这种IL-1作用。此外，组织学显示NOS2缺乏和抗IL-1治疗的小鼠软骨PG损失明显改善。在NOS2基因敲除杂合子小鼠中发现了中度软骨病理改变。
IL-1和NO在水肿和中性粒细胞流入中起次要作用，但在ZIA的软骨破坏中起主要作用。在这种小鼠关节炎模型中，软骨破坏在很大程度上是由PG合成的明显抑制和软骨细胞对IGF-1无反应引起的，这是由新合成的IL-1诱导并由NOS2激活介导的。
