Using inhibitors of metalloproteinases to treat arthritis. Easier said than done?
Using inhibitors of metalloproteinases to treat arthritis. Easier said than done?
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使用金属蛋白酶抑制剂治疗关节炎。
DOI：
10.1002/art.1780370802
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发表时间：
1994
影响因子：
--
通讯作者：
Brinckerhoff,CE
中科院分区：
文献类型：
--
作者：
Vincenti,MP;Clark,IM;Brinckerhoff,CE
胶原酶和基质溶解素在风湿性疾病中所见的细胞外基质的不可逆降解中具有首要作用。因此，毫不奇怪，相当多的注意力一直致力于发展战略，以减少其水平在患病关节。大多数努力集中在抑制酶的活性，通过增加天然抑制剂如TIMP的浓度，或通过引入将与酶复合并使其降解的合成化合物。也有针对抑制酶合成的研究。这些临床前研究已在无细胞和/或细胞培养系统和动物模型中进行。尽管有很好的临床前数据，但在临床竞技场中还没有惊人的成功。原因有几个。在某种程度上，它们植根于与设计具有高亲和力的酶活性抑制剂相关的技术困难，然后将它们递送到受影响的关节，同时仍然保持特异性和功效。构成关节软骨的蛋白多糖和胶原蛋白的复杂结构，沿着炎症滑膜组织的生物化学，只会加剧困难。除了这些技术问题之外，缺乏有关酶的生物化学和分子生物学的基础知识也阻碍了我们的努力。我们只是解决了金属蛋白酶的晶体结构（108），并开始了解控制基因表达的机制（67，68，70-72）。这些进展代表了金属蛋白酶酶学和生物学的重大成就，应该成为新一代有效疗法的科学基础。例如，从酶的晶体结构中获得的活性位点的知识可以促进开发在体内功能良好的紧密结合的特异性抑制剂。同样，基于我们目前对TIMP基因和MMP基因调控机制的理解，我们开始阐明如何打开或关闭这些基因，并有望相应地调节疾病。事实上，尽管一些研究仍处于临床前水平，但这些可能的方法正在成为现实（109）。关节炎疾病一般，特别是类风湿性关节炎，代表了一组复杂的多方面的临床疾病。临床症状和病理特征是由涉及急性和慢性炎症、免疫应答和金属蛋白酶生物化学的一系列生物途径引起的。（400字处截断摘要）
Collagenase and stromelysin have a premier role in the irreversible degradation of the extracellular matrix seen in rheumatic disease. It is therefore no surprise that considerable attention has been devoted to developing strategies to reduce their levels in diseased joints. Most efforts have focused on inhibiting the activity of the enzymes, either by increasing the concentration of natural inhibitors such as the TIMPs or by introducing into the joint synthetic compounds that will complex with the enzymes and inactivate them. There have also been studies directed at inhibiting enzyme synthesis. These preclinical studies have been carried out in cell-free and/or cell culture systems and in animal models. Despite promising preclinical data, there have been no stunning successes in the clinical arena. The reasons for this are several. In part, they are rooted in the technical difficulties associated with designing inhibitors of enzyme activity that are of high affinity, and then delivering them to the affected joints while still maintaining specificity and efficacy. The complicated structure of the proteoglycan and collagen that comprise articular cartilage, along with the biochemistry of inflamed synovial tissue, only compound the difficulties. In addition to these technical problems, the lack of fundamental knowledge about the biochemistry and molecular biology of the enzymes has handicapped our efforts. We are just resolving the crystal structure of the metalloproteinases (108) and beginning to understand the mechanisms controlling gene expression (67, 68, 70-72). These advances represent significant achievements in metalloproteinase enzymology and biology and should form the scientific basis for a new generation of effective therapies. For example, knowledge of the active site as derived from the crystal structure of the enzymes may facilitate the development of tightly-binding specific inhibitors which function well in vivo. Similarly, based on our current understanding of mechanisms controlling the regulation of both the TIMP genes and the MMP genes, we are beginning to elucidate how to turn these genes on or off, and hopefully, to modulate disease accordingly. Indeed, although some studies are still at a preclinical level, these possible approaches are becoming a reality (109). Arthritic diseases in general, and rheumatoid arthritis in particular, represent a complicated multifaceted set of clinical disorders. The clinical symptoms and pathologic features result from a cascade of biologic pathways that involve acute and chronic inflammation, the immune response, and metalloproteinase biochemistry.(ABSTRACT TRUNCATED AT 400 WORDS)