Elevated aggrecanase activity in a rat model of joint injury is attenuated by an aggrecanase specific inhibitor
Elevated aggrecanase activity in a rat model of joint injury is attenuated by an aggrecanase specific inhibitor
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DOI：
10.1016/j.joca.2010.12.004
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发表时间：
2011-03-01
影响因子：
7
通讯作者：
Morris, E. A.
中科院分区：
文献类型：
--
作者：
Chockalingam, P. S.;Sun, W.;Morris, E. A.
目的：通过测定大鼠关节液中聚集酶生成的ala - arg - gy -aggrecan （ARG-aggrecan）片段水平，评价大鼠创伤性膝关节损伤后的聚集酶活性，并与人膝关节损伤后向关节液中释放的ARG-aggrecan进行比较。目的观察小分子抑制剂对大鼠模型诱导的聚聚糖酶活性的影响。方法：采用酶联免疫吸附法（ELISA）测定动物和人关节液中arg -聚集蛋白的含量。采用大鼠半月板撕裂（MT）引起的关节不稳定模型，评估arg -聚集蛋白释放到关节液中以及聚合酶抑制的效果。急性关节损伤或骨关节炎患者的滑液也被采集，并检测arg -聚集蛋白。结果：与未受伤的对照受试者相比，膝关节损伤后患者关节液中arg -聚集蛋白水平显著提高。同样，在大鼠MT模型中，滑液arg -聚集蛋白水平在手术诱导的关节不稳定后增加，通过口服AGG-523（一种聚集酶特异性抑制剂）可以显著减弱。结论：聚集酶产生的聚集蛋白片段在膝关节损伤后迅速释放到人和大鼠关节液中，并在较长时间内保持升高。我们在人体和临床前模型中的发现加强了关节和膝关节损伤和疾病中聚集酶活性之间的联系。一种小分子聚聚糖酶抑制剂能够减少聚聚糖酶产生的聚集蛋白片段释放到大鼠关节中，这表明对人类聚聚糖酶活性的药物抑制可能是减缓关节损伤后软骨降解的有效治疗方法。(C) 2010年国际骨关节炎研究学会。Elsevier Ltd.出版。版权所有。
Objective: To evaluate aggrecanase activity after traumatic knee injury in a rat model by measuring the level of aggrecanase-generated Ala-Arg-Gly-aggrecan (ARG-aggrecan) fragments in synovial fluid, and compare with ARG-aggrecan release into joint fluid following human knee injury. To evaluate the effect of small molecule inhibitors on induced aggrecanase activity in the rat model.Method: An enzyme-linked immunosorbent assay (ELISA) was developed to measure ARG-aggrecan levels in animal and human joint fluids. A rat model of meniscal tear (MT)-induced joint instability was used to assess ARG-aggrecan release into joint fluid and the effects of aggrecanase inhibition. Synovial fluids were also obtained from patients with acute joint injury or osteoarthritis and assayed for ARG-aggrecan.Results: Joint fluids from human patients after knee injury showed significantly enhanced levels of ARG-aggrecan compared to uninjured reference subjects. Similarly, synovial fluid ARG-aggrecan levels increased following surgically-induced joint instability in the rat MT model, which was significantly attenuated by orally dosing the animals with AGG-523, an aggrecanase specific inhibitor.Conclusions: Aggrecanase-generated aggrecan fragments were rapidly released into human and rat joint fluids after injury to the knee and remained elevated over a prolonged period. Our findings in human and preclinical models strengthen the connection between aggrecanase activity in joints and knee injury and disease. The ability of a small molecule aggrecanase inhibitor to reduce the release of aggrecanase-generated aggrecan fragments into rat joints suggests that pharmacologic inhibition of aggrecanase activity in humans may be an effective treatment for slowing cartilage degradation following joint injury. (C) 2010 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.