Proteolytic enzymes in human cartilage: the pathogenesis of osteoarthritis.

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.