Lysine392, a K63-linked ubiquitination site in NEMO, mediates inflammatory osteoclastogenesis and osteolysis.

Alhawagri M, Yamanaka Y, Ballard D, Oltz E, Abu-Amer Y
J Orthop Res. 2012 30 (4): 554-60

PMID: 21913221 · PMCID: PMC3272311 · DOI:10.1002/jor.21555

PMMA particles released from bone implants are considered major contributor to osteolysis and subsequent implant failure. Although the ensuing inflammatory response has been described, the mechanisms underlying PMMA particulate-induced osteolysis remain enigmatic. In previous studies, we have established that activation of Nuclear factor kappa-B (NF-κB) 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-κB activation, dampens particle-induced osteolysis. The IKK complex consists of IKKα, IKKβ, and IKKγ, also known as NEMO. NEMO has no catalytic activity and serves as a scaffold protein facilitating assembly and distal activation of NF-κB signaling. In fact, blocking binding of NEMO with IKKα/β abolishes NF-κB activity. In the current study, we identify Lysine 392 residue in NEMO as crucial mediator of PMMA particle-induced inflammatory osteoclastogenesis and osteolysis. Using mice in which NEMO-K392R mutation has been introduced, we provide evidence that PMMA-induced osteoclasts and osteolytic responses are impaired. Furthermore, we show that this impairment is likely due to poor activation of NF-κB and Erk, but not other MAP kinases. Our findings suggest that NEMO Lysine392, a well-established K63-linked polyubiquitination site, is an important mediator of PMMA-induced osteolysis. Therefore, this NEMO motif should be considered as a target to combat PMMA particle-induced osteolysis.

Copyright © 2011 Orthopaedic Research Society.

MeSH Terms (19)

Animals Bone Resorption Extracellular Signal-Regulated MAP Kinases Germ-Line Mutation I-kappa B Proteins Intracellular Signaling Peptides and Proteins JNK Mitogen-Activated Protein Kinases Lysine Mice Mice, Mutant Strains Mutagenesis, Site-Directed Osteitis Osteoclasts Osteolysis p38 Mitogen-Activated Protein Kinases Polymethyl Methacrylate Prosthesis Failure Signal Transduction Ubiquitination

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