title: Lysine392, a K63-linked ubiquitination site in NEMO, mediates inflammatory osteoclastogenesis and osteolysis.
abstract: 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.
authors.affiliation: Department of Orthopaedics, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Alhawagri
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yamanaka
authors.forename: Dean
authors.initials: D
authors.lastname: Ballard
authors.forename: Eugene
authors.initials: E
authors.lastname: Oltz
authors.forename: Yousef
authors.initials: Y
authors.lastname: Abu-Amer
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000276:immunology / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D018095:Germ-Line Mutation; D020672:I-kappa B Proteins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D016297:Mutagenesis, Site-Directed; D010000:Osteitis / Q000276:immunology / Q000473:pathology; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D010014:Osteolysis / Q000276:immunology* / Q000473:pathology; D019904:Polymethyl Methacrylate / Q000494:pharmacology*; D011475:Prosthesis Failure; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D054875:Ubiquitination / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D020672:I-kappa B Proteins; D047908:Intracellular Signaling Peptides and Proteins; C514981:NEMO protein, mouse; D019904:Polymethyl Methacrylate; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D008239:Lysine