Steinmeyer J, Daufeldt S, Kalbhen D A
Institut für Pharmakologie und Toxikologie, Rheinische Friedrich-Wilhelms-Universität Bonn, Germany.
Res Exp Med (Berl). 1997;197(2):63-79. doi: 10.1007/s004330050056.
Matrix metalloproteinases (MMP) are among the key enzymes responsible for the proteolytic destruction of articular cartilage during chronic rheumatic diseases. Articular cartilage is one potential target for drugs designed to inhibit the activity of MMPs in order to stop or to slow down the proteolytic destruction of the extracellular matrix of cartilage. The purpose of this study was to investigate the effect of the synthetic inhibitor of MMPs U-24522 for its ability (1) to inhibit in vitro the activity of MMP-proteoglycanases; (2) to modulate the morphology and viability of cartilage explants; and (3) to modify the biosynthesis and release of proteoglycans from articular cartilage explants. U-24522 dose-dependently inhibited the activity of MMP-proteoglycanases and significantly reduced the release of proteoglycans from interleukin-1 treated bovine articular cartilage explants when tested at concentrations ranging from 10(-4) to 10(-9) M. This hydroxamic acid derivative proved not to be harmful to chondrocyte viability and cartilage morphology. In addition, U-24522 had no effect on the rate of proteoglycan biosynthesis of interleukin-1 treated cartilage explants and increased the percentage of newly synthesized proteoglycans to form macromolecular aggregates. Thus U-24522 combines direct inhibitory potential on the activity of MMP-proteoglycanases with the inhibition of interleukin-1 stimulated proteoglycan loss from articular cartilage explants without affecting the morphology, viability and biosynthesis of proteoglycans of bovine articular cartilage explants.
基质金属蛋白酶（MMP）是慢性风湿性疾病期间导致关节软骨蛋白水解破坏的关键酶之一。关节软骨是旨在抑制MMP活性以阻止或减缓软骨细胞外基质蛋白水解破坏的药物的一个潜在靶点。本研究的目的是研究MMP合成抑制剂U - 24522的作用，以考察其（1）在体外抑制MMP - 蛋白聚糖酶活性的能力；（2）调节软骨外植体形态和活力的能力；（3）改变关节软骨外植体中蛋白聚糖生物合成和释放的能力。当在10^(-4)至10^(-9) M的浓度范围内进行测试时，U - 24522呈剂量依赖性地抑制MMP - 蛋白聚糖酶的活性，并显著减少白细胞介素 - 1处理的牛关节软骨外植体中蛋白聚糖的释放。这种异羟肟酸衍生物被证明对软骨细胞活力和软骨形态无害。此外，U - 24522对白细胞介素 - 1处理的软骨外植体中蛋白聚糖的生物合成速率没有影响，并且增加了新合成的蛋白聚糖形成大分子聚集体的百分比。因此，U - 24522兼具对MMP - 蛋白聚糖酶活性的直接抑制潜力以及抑制白细胞介素 - 1刺激的关节软骨外植体中蛋白聚糖丢失的能力，同时不影响牛关节软骨外植体的形态、活力和蛋白聚糖的生物合成。
