Osteolysis, due to particulate wear debris, is the major cause of implant failure following total joint arthroplasty. While the osteolytic bone resorption, loosened prosthesis are associated with formation, at the implant bone interface, of a fibrous """"""""membrane"""""""" containing abundant mono and multinuclear tissue macrophages, many of which are bound to, or have ingested implant-derived wear particles. It appears, therefore, that implant debris prompts a granulomatous foreign body reaction, which, in turn, releases molecules capable of recruiting abundant osteoclasts eventuating in osteolysis and implant failure. Tumor necrosis factor-alpha (TNF), among the most potent of osteoclastogenic cytokines, is present in implant-derived tissues and induced in vitro and in vivo by implant particles. Moreover, an abundance of evidence points to a circumstance in which macrophages, activated by wear particles, secrete TNF which prompts osteoclast recruitment and perhaps enhances the resorptive capacity of mature osteoclasts. We therefore hypothesize: 1. Implant particles induce macrophage TNF expression; 2. TNF plays an essential role in particle-stimulated osteoclast formation and/or function, in vitro. 3. TNF plays an essential role in particle-stimulated osteoclast formation and/or function, in vivo. Thus, our Specific Aims are to: 1. DETERMINE THE MOLECULAR MECHANISMS BY WHICH IMPLANT PARTICLES INDUCE MACROPHAGE TNF EXPRESSION; 2. DETERMINE THE ROLE OF TNF IN PARTICLE-STIMULATED OSTEOCLAST RECRUITMENT AND/OR FUNCTION, IN VITRO; 3. DETERMINE THE ROLE OF TNF IN PARTICLES-STIMULATE OSTEOCLAST RECRUITMENT AND/OR FUNCTION, IN VIVO. We believe these goals are in reach as we have in hand 1) a number of TNF promoter reporter constructs and a particle-responsive, TNF-producing, transferable macrophage cell line, 2) a variety of transgenic mice with altered capacity to respond to TNF, and 3) an in vivo murine model of implant osteolysis mimicking the human situation.
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