{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T23:27:45Z","timestamp":1773790065558,"version":"3.50.1"},"reference-count":40,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2008,7,24]],"date-time":"2008-07-24T00:00:00Z","timestamp":1216857600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal Orthopaedic Research"],"published-print":{"date-parts":[[2008,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Particle\u2010induced periprosthetic osteolysis is the major cause for orthopedic implant failure. This failure is mediated mainly by the action of osteoclasts, the principal cells responsible for bone resorption and osteolysis. Therapeutic interventions to alleviate osteolysis have been focused on understanding and targeting mechanisms of osteoclastogenesis. The nuclear transcription factor NFAT is an essential terminal differentiation factor of osteoclastogenesis. This transcription factor is known to cooperate with c\u2010jun\/AP\u20101 in mediating RANKL\u2010induced osteoclastogenesis. We have previously determined that RANKL is an essential cytokine mediator of particle\u2010induced osteoclastogenesis, and that PMMA particles activate JNK and c\u2010jun\/AP\u20101 in bone marrow macrophages (osteoclast precursors). In the current study, we investigated the effect of PMMA particles on the NFAT signaling pathway in osteoclast precursor cells. Our findings point out that PMMA particles stimulate nuclear translocation of NFAT2 in wild\u2010type osteoclast precursors, which is associated with increased osteoclastogenesis. More importantly, induction of osteoclastogenesis was selectively blocked in a dose\u2010dependent fashion by the calcineurin inhibitors, Cyclosporine\u2010A and FK506. Further, this activation was also blocked in a time\u2010dependent fashion by the NFAT inhibitor VIVIT. Finally, we provide novel evidence that PMMA particles induce binding of NFAT2 and AP\u20101 proteins. Thus, our findings demonstrate that activation of the NFAT pathway in conjunction with MAP kinases is essential for basal and PMMA\u2010stimulated osteoclastogenesis. \u00a9 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. 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