I am an assistant professor of orthopedic surgery as Washington University with clinical subspeciality interest in orthopedic oncology and total joint replacement surgery. Approximately two years ago I began studying one mechanisms of particle induced osteolysis in the laboratory of Dr. Steven L. Teitelbaum. During this time significant progress has been made in elucidating the mechanisms by which implant particles provoke osteolysis (detailed in preliminary data). A mentored clinical scientist development award would allow me to increase the amount of time devoted to research with the ultimate goal to accelerate developing to independent research status. The present research proposal relates to implant osteolysis, the major cause of implant failure following total joint arthroplasty. While the osteolytic process is due to osteoclastic 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 nd implant failure. I have shown that 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 enhanced bone resorption. We therefore hypothesize: 1. TNF plays an pivotal role in particle-stimulated osteoclast formation and/or function, in vitro. 2. TNF plays an pivotal role in particle stimulated osteoclast formation and/or function, in vivo. Thus, our Specific Aims are to: 1. DETERMINE THE ROLE OF TNF IN PARTICLE-STIMULATED OSTEOCLAST RECRUITMENT AND/OR FUNCTION, IN VITRO; 2. DETERMINE THE ROLE OF TNF IN PARTICLE-STIMULATED OSTEOCLAST RECRUITMENT AND/OR FUNCTION, IN VIVO. We believe these goals are in reach as we have in hand 1) a well characterized osteoclast differentiation assay, 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.
