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首页> 外文期刊>Osteoarthritis and cartilage >Elevated aggrecanase activity in a rat model of joint injury is attenuated by an aggrecanase specific inhibitor.
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Elevated aggrecanase activity in a rat model of joint injury is attenuated by an aggrecanase specific inhibitor.

机译：在大鼠关节损伤模型中，软骨聚集蛋白聚糖酶的活性被软骨聚集蛋白聚糖特异性抑制剂抑制。

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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.
机译：目的：通过测量滑膜液中软骨聚集蛋白聚糖生成的Ala-Arg-Gly-aggrecan（ARG-aggrecan）片段的水平，评估大鼠外伤性膝关节损伤后软骨聚集蛋白聚糖酶的活性，并与ARG-aggrecan释放至关节液后进行比较人的膝盖受伤。为了评估小分子抑制剂对大鼠模型中诱导的软骨聚集蛋白聚糖酶活性的影响。方法：建立了一种酶联免疫吸附测定（ELISA）来测量动物和人关节液中ARG-aggrecan的水平。使用半月板撕裂（MT）引起的关节不稳定性的大鼠模型评估ARG-aggrecan释放到关节液中和聚集蛋白聚糖酶抑制的作用。还从患有急性关节损伤或骨关节炎的患者中获得了滑液，并分析了ARG-aggrecan。结果：与未受伤的参考对象相比，膝关节损伤后人类患者的关节液显示ARG-aggrecan的水平显着提高。同样，在大鼠MT模型中，由于手术引起的关节不稳定，滑液ARG-aggrecan的水平升高，而口服aggrecanase特异性抑制剂AGG-523则明显减轻了滑膜液中ARG-aggrecan的水平。结论：在膝盖受伤后，由农用葡聚糖酶产生的聚集蛋白聚糖片段迅速释放到人和大鼠的关节液中，并长期保持升高状态。我们在人类和临床前模型中的发现加强了关节中软骨聚集蛋白聚糖酶活性与膝盖受伤和疾病之间的联系。小分子软骨聚集蛋白聚糖酶抑制剂减少软骨聚集蛋白聚糖酶活性的药理学抑制作用可能是减缓关节损伤后软骨降解的有效方法。

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