Docherty A J, Murphy G
Celltech Ltd, Slough, UK.
Ann Rheum Dis. 1990 Jun;49 Suppl 1:469-79.
Loss of connective tissue integrity occurs in many disease processes, including rheumatoid arthritis and osteoarthritis. Although there is a high incidence of these diseases in the developed world, there is no treatment that prevents the tissue damage that occurs. Several lines of evidence suggest that uncontrolled connective tissue metalloproteinase activity is responsible for the damage, and as a consequence the inhibition of these enzymes has become the target for therapeutic intervention. Several connective tissue metalloproteinases, including collagenase, stromelysin, and gelatinase, together with tissue inhibitors of metalloproteinases (TIMPs), have been described. Because of difficulties in isolating the metalloproteinases in sufficient quantity as pure separate enzymes, however, very little knowledge has accumulated about their detailed biochemistry. For similar reasons the way in which TIMPs inhibit tissue metalloproteinases is not yet fully understood. In this article it is shown how cloning metalloproteinase and TIMP cDNAs can provide information about the structure of these enzyme and inhibitor families and how the cDNAs can be used to generate recombinant cell lines from which enzymes and inhibitors can be readily purified for further studies.
结缔组织完整性的丧失发生在许多疾病过程中，包括类风湿性关节炎和骨关节炎。尽管这些疾病在发达国家的发病率很高，但尚无预防组织损伤的治疗方法。多条证据表明，结缔组织金属蛋白酶活性失控是造成损伤的原因，因此抑制这些酶已成为治疗干预的目标。已经描述了几种结缔组织金属蛋白酶，包括胶原酶、基质溶解素和明胶酶，以及金属蛋白酶组织抑制剂（TIMPs）。然而，由于难以大量分离出纯净的单一金属蛋白酶，关于它们详细生物化学的知识积累很少。出于类似原因，TIMP抑制组织金属蛋白酶的方式尚未完全了解。本文展示了克隆金属蛋白酶和TIMP cDNA如何能够提供有关这些酶和抑制剂家族结构的信息，以及这些cDNA如何用于生成重组细胞系，从中可以很容易地纯化出酶和抑制剂用于进一步研究。
