Inflammatory osteolysis induced by implant-derived wear debris is the main cause of total joint replacement failure and remains the major clinical problem in total joint arthroplasty patients. It is accepted that aseptic loosening is associated with infiltration and recruitment of macrophages, neutrophils, lymphocytes, fibroblasts and other cell-types to the implant-bone interface. These processes are associated with abundant secretion of pro-inflammatory cytokines and activation of proteinases that together lead to propagation of the localized inflammatory response and periprosthetic bone erosion. Recent evidence indicates that members of the tumor necrosis factor (TNF) family play a key role in modulating osteolysis. Specifically, TNF and RANKL are known as direct recruiters of osteoclast precursor cells, inducers of differentiation and activation of osteoclasts, the cells responsible for the bone lesion. Previous and current data indicate that polymethylmethacrylate (PMMA) particles may exert their osteoclastic effects directly, indirectly through mediation of pro-inflammatory cytokines, or a combination of both. In this regard, we have documented recently that, in multi-cell type mixed marrow cultures, RANKL (secreted by stromal cells) and TNF-alpha (secreted by osteoclast precursors and stromal cells) activate NFkappaB and, at least in part, mediate PMMA-induced osteoclastogenesis. Equally important, given the important role of MAP kinases in osteoclasts we investigated whether these kinases play a role in PMMA particle-induced osteoclastogenesis and osteolysis. In this regard, we found that PMMA particles directly activate the MAP kinases p38 and Erkl/2 (p42/p44) in osteoclast precursors, and selective inhibition of either kinase reduced osteoclastogenesis. These observations led us to hypothesize that p38 and ERK kinases may play a key role in the development of inflammatory osteolysis. This hypothesis is supported by recent findings indicating that pharmacological inhibition of p38 arrests osteoclast development. Thus our Specific Aims are to, (1) delineate the mechanism(s) by which PMMA particles activate MAP kinase pathways in osteoclast precursors, and (2) inhibit inflammatory osteolysis, in vivo, by blocking PMMA particle-induced p38 and Erkl/2 activation.
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