Expression of gelatinase A and its activator MT1-MMP in the inflammatory periprosthetic response to polyethylene

Wear debris of polyethylene prosthetic components is known to induce a hose granulomatous reaction which recruits numerous macrophages and multinuclea ted giant cells, By releasing cellular mediators of a nonspecific inflammat ory reaction, activated phagocytic cells are thought to play: a key role in osteolysis leading to aseptic loosening of the prosthesis. Matrix metallop roteinases (MMPs) have been implicated in this destructive process by their ability to degrade extracellular matrix components of bone and adjacent co nnective tissue. To investigate the roles of gelatinase A, its activator MT 1-MMP, and the MMP inhibitors TIMP-1 and TIMP-2 in aseptic loosening of pol yethylene prostheses, immunohistochemistry (WC) and in situ hybridization ( ISH) were performed on periprosthetic pseudosynovial interface tissues. Gel atinase A and MT1-MMP were strongly detected immunohistochemically in macro phages and multinucleated giant cells in contact with polyethylene wear deb ris, In contrast to MT1-MMP, gelatinase A mRNAs were not found in phagocyti c cells but in surrounding fibroblasts, thereby suggesting cooperation betw een macrophages and fibroblasts in this process. While TIMP-1 was expressed essentially in hyperplastic pseudosynoviocytes as assessed by MC and LSH, TIMP-2, MT1-MMP, and gelatinase a were colocalized in phagocytic cells. The se data support the concept of progelatinase A activation involving a trimo lecular complex (MT1-MMP-TIMP-2-gelatinase A) mechanism. Thus, this study d emonstrated that gelatinase A and its activator might contribute to the ase ptic loosening of polyethylene prostheses.