Otterness I G, Bliven M L, Milici A J, Poole A R
Department of Immunology and Infectious Diseases, Pfizer Inc., Groton, Connecticut.
Am J Pathol. 1994 May;144(5):1098-108.
Arthritis refers to a heterogeneous class of diseases characterized by impairment of movement. Yet animal models of arthritis have traditionally been based on the utilization of animals housed without the capability of extended free movement and without adjunctive measurement of mobility. To define the determinants of mobility impairment, we have established a lipopolysaccharide (LPS)-induced arthritis model in the hamster that prominently features monitoring of mobility and compares mobility changes with histological and biochemical changes during arthritis. Intraarticular LPS induces a dose-dependent inhibition of the hamster's mobility as measured by decreased daily distance on a running wheel (normal distance 9 to 12 km/day). At low concentrations of LPS (0.1 and 1 microgram/knee), daily distances returned to normal after 4 and 6 days, respectively. At higher concentrations, the mobility was still markedly suppressed after 6 days, and, at 100 micrograms/knee, irreversible chondrocyte loss was observed on the femoral condylar margins. Further studies were therefore conducted using 1 microgram LPS/knee. Histological and biochemical changes were examined to determine which resolved at the time of restoration of mobility. At the time of restoration of mobility, the synovial capsule was still edematous and heavily infiltrated with leukocytes; proteoglycan loss from the medial femoral condyle was still increasing. Plasma keratan sulfate failed to correlate with either proteoglycan loss or mobility changes. Proteoglycan synthesis, which was maximally suppressed the second day after LPS, was enhanced over controls at the time of restoration of mobility, suggesting the onset of repair. These results suggest a possible association of mobility inhibition with local cytokine synthesis. This model provides an approach to define the causes of mobility impairment.
关节炎指的是一类以运动功能受损为特征的异质性疾病。然而，传统的关节炎动物模型一直基于使用那些被圈养且无法自由进行长时间活动的动物，并且没有对活动能力进行辅助测量。为了确定运动功能受损的决定因素，我们在仓鼠中建立了一种脂多糖（LPS）诱导的关节炎模型，该模型的显著特点是对活动能力进行监测，并将关节炎期间的活动变化与组织学和生化变化进行比较。关节内注射LPS会导致仓鼠活动能力受到剂量依赖性抑制，通过测量其在跑轮上的每日跑动距离来评估（正常距离为每天9至12公里）。在低浓度LPS（0.1和1微克/膝关节）时，每日跑动距离分别在4天和6天后恢复正常。在较高浓度时，6天后活动能力仍受到明显抑制，而在100微克/膝关节时，在股骨髁边缘观察到不可逆的软骨细胞损失。因此，我们使用1微克LPS/膝关节进行了进一步研究。对组织学和生化变化进行检查，以确定哪些在活动能力恢复时得到解决。在活动能力恢复时，滑膜囊仍然水肿，并有大量白细胞浸润；股骨内侧髁的蛋白聚糖损失仍在增加。血浆硫酸角质素与蛋白聚糖损失或活动变化均无相关性。蛋白聚糖合成在LPS注射后第二天受到最大程度抑制，在活动能力恢复时比对照组增强，提示修复开始。这些结果表明活动抑制可能与局部细胞因子合成有关。该模型为确定运动功能受损的原因提供了一种方法。
