Neutral proteinases and their inhibitors in the loosening of total hip prostheses.

This study demonstrated the profile of the neutral proteinases, i) matrix metalloproteinases (MMP)-1, -2, -3, and -9, and ii) serine proteinases, elastase, cathepsin G, urokinase and tissue type plasminogen activators (uPA and tPA) as well as their inhibitors, namely, tissue inhibitor of matrix metalloproteinases (TIMP)-1, alpha 1-antitrypsin, alpha 1-antichymotrypsin, plasminogen activator inhibitor (PAI)-1 & 2, around loose hip prostheses to clarify the step in the cascade of biological host response in the loosening of replaced total hip joints. Immunohistochemical analysis showed the presence of MMPs (MMP-1, -2, -3, and -9) and serine proteinases (elastase, cathepsin G, uPA and tPA) both in the interface tissues and pseudocapsular tissues. Functional biochemical analysis revealed elevated proteolytic activities of MMPs, especially, MMP-2 and MMP-9, and also elastase and cathepsin G, which were not inhibited in loco, although the inhibitors, TIMP-1, alpha 1-antitrypsin and alpha 1-antichymotrypsin were detected. The results suggested the imbalance of neutral proteinase-inhibitor levels around loose hip prostheses. The proteolytic enzyme in the interface tissues could directly weaken periprosthetic tissues. The pseudocapsular tissues may induce cellular host response and proteolytic activation. Thus, the pseudocapsular tissues could contribute to the loosening via production of MMPs and serine proteinases into the synovial fluid. Pseudosynovial fluid, which showed high contents of inhibitors (TIMP-1, alpha 1-antitrypsin and alpha 1-antichymotrypsin) associated with low proteolytic potentials, could be produced to prevent the unfavorable elevation of proteolytic enzymes in loco as a local host response to implants.