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The inflammatory microenvironment supports recruitment and differentiation of osteoclasts, the primary culprit of osteolysis. Therefore, understanding the complex signals that contribute to osteoclastogenesis and osteolysis is a sensible approach to design strategies to inhibit bone loss. The signaling cascades that coordinate osteoclastogenesis have been widely investigated. These include MAP kinases, Akt\/PI3K pathway, NF\u2010\u03baB signal transduction pathway, and NFAT pathway. We have recently reported that polymethylmethacrylate (PMMA) particles activate the NFAT pathway in murine osteoclast precursors and that NFAT inhibitors dose\u2010dependently block PMMA\u2010induced osteoclastogenesis. In the current study, we examined the role of JNK and NFATc1 in mice in response to PMMA particles using murine calvaria model. We show that locally administered MAPK\/JNK inhibitor SP600125 and calcineurin\/NFAT inhibitor cyclosporine\u2010A effectively blocked PMMA\u2010induced osteolysis in murine calvaria. To buttress the clinical relevance of JNK\/NFATc1\u2010based regulation of PMMA\u2010induced osteoclastogenesis, we evaluated the effect of PMMA using human macrophages. We demonstrate that SP600125 and cyclosporine\u2010A abolished particle\u2010induced osteoclastogenesis in human osteoclast progenitors retrieved from patients undergoing total hip replacement. Thus JNK and NFATc1 appear to act as significant mediators of orthopedic particle\u2010induced osteolysis in humans. \u00a9 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. 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