This chapter summarizes the role of neutral proteinases in rheumatoid arthritis. Proteoglycans in cartilage exist as aggregates of large molecular weight (MW) polyanionic species of 100 or more glycosaminoglycan chains attached 0-xylosidically to the serine residue of a large protein core. Degradation of proteoglycans at neutral pH usually involves proteolytic activity along the protein core of the molecule. This cleavage leads to proteoglycan solubilization releasing glycosaminoglycan chains that facilitates the susceptibility of collagen to degradation. Leukocytic cathepsin G is a chymotryptic-like serine protease that has been demonstrated to break down proteoglycans and type II collagen from articular cartilage at neutral pH. The PMN collagenase is a thiol-metalloproteinase that specifically degrades native collagen fibrils at neutral pH. Macrophages are also phagocytic cells that enter the joint space in response to chemotactic stimuli. Collagenase released from activated macrophages is a typical metallo-enzyme mostly present in latent form that can be activated by other proteases, such as trypsin and plasmin. The interface between articular cartilage and proliferating pannus represents the area, in which maximal progressive destruction of the joint occurs in RA patients. Neutral proteases are released by cartilage cells in the presence of products of lipopolysaccharide stimulated macrophages. Many of the naturally occurring serum proteins that inhibit the cell derived neutral proteinases have been purified and well characterized. Some of the most interesting protease inhibitors have been derived from bacterial sources and plant sources. Inhibitors of neutral poteases are widely distributed in animal tissues. Specificity among the enzymes arises when secondary amino acids at the active site differ in position, size, or degree of hydrophobicity. The development of inhibitors of proteases must take into account such problems as enzyme and tissue specificity and toxicity; although in vivo, toxicity may be diminished by homeostatic resynthesis of enzymes and other protein constituents.
ASJC Scopus subject areas
- Organic Chemistry