Sapolsky A, Howell D
Compr Ther. 1976 Oct;2(10):33-40.
It is evident that human articular cartilage possesses, in addition to multiple forms of cathepsin D, multiple forms of other acid cathepsins, and, most important, a family of at least four closely related neutral protease enzyme forms, all of which degrade proteoglycan. In addition, caseinase and histonase activities are present. The search for these enzymes in human cartilage ahs been presented in some detail in order to give an idea of some of the problems faced in such research, as well as the hypotheses and hopes that flow from it and prepare the ground for further research. The actual role of proteolytic enzymes in the physiologic and pathologic condition of cartilage remains to be determined. It is hoped that these enzymes, especially the neutral protease forms, will be sufficiently purified to enable preparation of antibodies to them. This will help to clarify what controls their release from the chondrocytes and where they function in the cartilage. Meanwhile, it seems appropriate to study the neutral protease forms and their role in initiating the degradation of proteoglycan in the early stages of osteoarthritis. The chief role of cathepsin D and the new acid cathepsins is most likely in intracellular digestion. One may hypothesize a three-step sequence of the degradation of the matrix proteoglycan: (1) initial extracellular attack by the neutral matrix, (2) endocytosis of the fragments by the cells, and (3) completion of their degradation within the lysosomal digestive system of the cell. The initial degradation of the matrix proteoglycan would facilitate the entrance of other degrading enzymes from the synovium to aid in total destruction of the cartilage. While awaiting knowledge of the primary events that trigger the development of osteoarthritis, enzymatic research offers the real hope of finding a way to control the enzymatic degradation of proteoglycan occurring in the early stages of the disease. Research into the nature of these degrading enzymes will lead to the development of therapeutically suitable inhibitors.
显然，人类关节软骨除了含有多种形式的组织蛋白酶D外，还含有多种形式的其他酸性组织蛋白酶，最重要的是，含有一个由至少四种密切相关的中性蛋白酶酶形式组成的家族，所有这些都能降解蛋白聚糖。此外，还存在酪蛋白酶和组蛋白酶活性。为了让人们了解此类研究中面临的一些问题，以及由此产生的假设和希望，并为进一步研究奠定基础，已经较为详细地介绍了在人类软骨中寻找这些酶的过程。蛋白水解酶在软骨的生理和病理状况中的实际作用仍有待确定。希望这些酶，尤其是中性蛋白酶形式，能够得到充分纯化，以便制备针对它们的抗体。这将有助于阐明是什么控制了它们从软骨细胞中的释放以及它们在软骨中的作用位置。与此同时，研究中性蛋白酶形式及其在骨关节炎早期启动蛋白聚糖降解中的作用似乎是合适的。组织蛋白酶D和新的酸性组织蛋白酶的主要作用很可能是在细胞内消化。人们可以假设基质蛋白聚糖降解的三步序列：(1) 中性基质的初始细胞外攻击，(2) 细胞对片段的内吞作用，以及(3) 在细胞的溶酶体消化系统内完成它们的降解。基质蛋白聚糖的初始降解将促进来自滑膜的其他降解酶的进入，以帮助完全破坏软骨。在等待了解引发骨关节炎发展的主要事件的同时，酶学研究为找到控制疾病早期发生的蛋白聚糖酶促降解的方法提供了真正的希望。对这些降解酶性质的研究将导致开发出治疗上合适的抑制剂。
