Munteanu S E, Ilic M Z, Handley C J
La Trobe University, Bundoora, Victoria, Australia.
Arthritis Rheum. 2000 Oct;43(10):2211-8. doi: 10.1002/1529-0131(200010)43:10<2211::AID-ANR8>3.0.CO;2-D.
The catabolism of aggrecan and loss of aggrecan fragments from articular cartilage is a key event in the pathogenesis of arthritic diseases such as osteoarthritis. The catabolism of aggrecan is mediated by the specific proteolytic activity termed aggrecanase. The aim of this study was to investigate the effect of the chondroprotective agent calcium pentosan polysulfate (CaPPS) on the aggrecanase-mediated catabolism of aggrecan.
The catabolism of 35S-labeled aggrecan and loss of tissue glycosaminoglycans (GAGs) were investigated using bovine articular cartilage explant cultures maintained in medium containing varying concentrations of CaPPS (1-100 microg/ml) in the presence or absence of 10(-6)M retinoic acid or 7 ng/ml recombinant human interleukin-1alpha (rHuIL-1alpha). In addition, the effect of CaPPS on the degradation of aggrecan monomers by aggrecanase activity present in conditioned medium from joint capsule explant cultures was investigated.
CaPPS inhibited the catabolism of 35S-labeled aggrecan in a dose-dependent manner, particularly when retinoic acid or rHuIL-1alpha was used to stimulate aggrecan catabolism. These effects were reflected in the tissue levels of GAG remaining in these cultures at the end of the experiment. CaPPS inhibited the degradation of aggrecan monomers by soluble aggrecanase activity.
CaPPS inhibits the catabolism of aggrecan by articular cartilage in a dose-dependent manner, particularly when the processes responsible for aggrecan loss are stimulated. This effect occurs, at least in part, through direct inhibition of aggrecanase activity. CaPPS did not adversely affect overall chondrocyte metabolism, as shown by the incorporation of 35S-sulfate and 3H-leucine into macromolecules and by lactate production in cartilage explant cultures.
蛋白聚糖的分解代谢以及关节软骨中蛋白聚糖片段的丢失是骨关节炎等关节炎性疾病发病机制中的关键事件。蛋白聚糖的分解代谢由一种名为蛋白聚糖酶的特异性蛋白水解活性介导。本研究的目的是探讨软骨保护剂聚硫酸戊聚糖钙（CaPPS）对蛋白聚糖酶介导的蛋白聚糖分解代谢的影响。
在含有不同浓度CaPPS（1 - 100微克/毫升）的培养基中，在有或无10⁻⁶M视黄酸或7纳克/毫升重组人白细胞介素-1α（rHuIL-1α）存在的情况下，使用牛关节软骨外植体培养物研究³⁵S标记的蛋白聚糖的分解代谢和组织糖胺聚糖（GAG）的丢失。此外，研究了CaPPS对关节囊外植体培养物条件培养基中存在的蛋白聚糖酶活性介导的蛋白聚糖单体降解的影响。
CaPPS以剂量依赖性方式抑制³⁵S标记的蛋白聚糖的分解代谢，特别是当使用视黄酸或rHuIL-1α刺激蛋白聚糖分解代谢时。这些作用反映在实验结束时这些培养物中剩余的GAG的组织水平上。CaPPS抑制可溶性蛋白聚糖酶活性对蛋白聚糖单体的降解。
CaPPS以剂量依赖性方式抑制关节软骨对蛋白聚糖的分解代谢，特别是当导致蛋白聚糖丢失的过程受到刺激时。这种作用至少部分是通过直接抑制蛋白聚糖酶活性发生的。如³⁵S-硫酸盐和³H-亮氨酸掺入大分子以及软骨外植体培养物中乳酸产生所示，CaPPS对软骨细胞的整体代谢没有不利影响。
