Total joint replacement with metallic and polymeric materials has provided dramatic relief of pain and improvement in function for millions of patients with end stage arthritis. Despite the success of joint replacement surgery, periprosthetic osteolysis in the presence or absence of aseptic loosening jeopardizes the long-term success of both cemented and cementless total joint replacements. Particulate debris derived from the prosthesis and (when present) bone cement is phagocytized, and it is believed that these particulates activate macrophages and osteoblasts (and perhaps fibroblasts) to produce factors which stimulate bone resorption. In support of this hypothesis, it has been demonstrated that cells from the periprosthetic granulomatous tissues and macrophage cell lines stimulated with particulates yield high levels of cytokines/growth factors and prostaglandin E/2 (PGE/2) associated with increased bone resorption in organ cultures. We propose to investigate this hypothesis by studying factors at the molecular and cellular levels which may trigger, maintain and/or regulate particulate-induced periprosthetic osteolysis. We will determine the most effective particulate species which activate """"""""standard"""""""" cell lines in vitro and correlate these findings with in vivo localization of activated cells (in the presence of particulates) in the periprosthetic osteolytic lesions measuring a select group of """"""""bone resorbing"""""""" cytokines, metalloproteinases and PGE/2. In addition, cells of the periprosthetic tissue will be isolated, characterized and then their ability to express bone resorbing agents will be determined. This proposal will concentrate on three as yet poorly understood aspects of implant-associated, periprosthetic osteolysis: (1) is there a dominant particulate species which is the stimulus to bone resorption or is this process a synergistic interaction among multiple particulate species? (2) Is there a dominant cell type which responds to the stimulus of wear debris or is the particulate-induced bone resorption a complex mechanism involving simultaneously multiple cell types (macrophages, fibroblasts, giant cells, osteoblasts and osteoclasts)?, and (3) is there a common regulatory mechanism at the cellular level which leads to periprosthetic osteolysis in cemented and cementless total hip arthroplasties? With regard to the first question, it should be stressed that the answer may have important implications for future implant design, fabrication and material selection. With regard to the second and third questions, there is a dearth of such information, which is deemed critical for the development of therapeutic modalities to prevent, retard or reverse implant-associated periprosthetic osteolysis.
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