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In previous studies, we have established that activation of Nuclear factor kappa\u2010B (NF\u2010\u03baB) and MAP kinase pathways plays a central role in the pathogenesis of inflammatory osteolysis. Specifically, we have shown that impeding IKK complex assembly, and thus subsequent NF\u2010\u03baB activation, dampens particle\u2010induced osteolysis. The IKK complex consists of IKK\u03b1, IKK\u03b2, and IKK\u03b3, also known as NEMO. NEMO has no catalytic activity and serves as a scaffold protein facilitating assembly and distal activation of NF\u2010\u03baB signaling. In fact, blocking binding of NEMO with IKK\u03b1\/\u03b2 abolishes NF\u2010\u03baB activity. In the current study, we identify Lysine 392 residue in NEMO as crucial mediator of PMMA particle\u2010induced inflammatory osteoclastogenesis and osteolysis. Using mice in which NEMO\u2010K392R mutation has been introduced, we provide evidence that PMMA\u2010induced osteoclasts and osteolytic responses are impaired. Furthermore, we show that this impairment is likely due to poor activation of NF\u2010\u03baB and Erk, but not other MAP kinases. Our findings suggest that NEMO Lysine392, a well\u2010established K63\u2010linked polyubiquitination site, is an important mediator of PMMA\u2010induced osteolysis. Therefore, this NEMO motif should be considered as a target to combat PMMA particle\u2010induced osteolysis. \u00a9 2011 Orthopaedic Research Society. \u00a9 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 30:554\u2013560, 2012<\/jats:p>","DOI":"10.1002\/jor.21555","type":"journal-article","created":{"date-parts":[[2011,9,12]],"date-time":"2011-09-12T17:10:02Z","timestamp":1315847402000},"page":"554-560","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Lysine392, a K63\u2010linked ubiquitination site in NEMO, mediates inflammatory osteoclastogenesis and 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