title: Inhibition of IKK activation, through sequestering NEMO, blocks PMMA-induced osteoclastogenesis and calvarial inflammatory osteolysis.
abstract: Osteoclasts, the primary bone-resorbing cells, play a crucial role in periprosthetic bone loss in response to implant-derived wear debris. Differentiation and activation of osteoclasts at the implant-bone interface are fueled by elevated levels of locally secreted inflammatory cytokines that heighten the osteolytic response. Among these cytokines are members of the TNF superfamily, including TNF and RANKL, which primarily act through activation of the transcription factor NF-kappaB. Activation of NF-kappaB is required for osteoclast formation, and its inhibition hampers osteoclastogenesis and bone loss. Activation of NF-kappaB is permitted following its dissociation from the inhibitory protein IkappaBalpha, an event subsequent to phosphorylation of the latter protein by the upstream IkappaBalpha kinase (IKK) complex. Our recent findings show that attenuating IKK complex assembly, by using a short peptide termed NEMO-binding domain (NBD) peptide, that blocks binding of IKK2 and IKK1 to IKKgamma/NEMO, inhibits NF-kappaB activation, and arrests RANKL-induced osteoclastogenesis. In this study, we examined if NBD is capable of blocking inflammatory osteolysis by PMMA particles. Our findings indicate that NBD peptide inhibits PMMA-induced IKK2 and NF-kappaB activation. More importantly, this peptide potently arrests PMMA-stimulated osteoclastogenesis and alleviates PMMA-induced inflammatory and osteolytic responses in mice. Thus, NBD peptide is considered as a promising modality to regulate inflammatory osteolysis.
authors.affiliation: Department of Orthopaedics and Cell Biology & Physiology, Washington University School of Medicine, One Barnes Hospital Plaza, 11300 West Pavilion Campus, Box 8233, St. Louis, Missouri 63110, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Clohisy
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yamanaka
authors.forename: Roberta
authors.initials: R
authors.lastname: Faccio
authors.forename: Yousef
authors.initials: Y
authors.lastname: Abu-Amer
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D051550:I-kappa B Kinase / Q000187:drug effects* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010010:Osteoclasts / Q000187:drug effects*; D010014:Osteolysis / Q000517:prevention & control*; D010446:Peptide Fragments / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D019904:Polymethyl Methacrylate / Q000009:adverse effects*; D017434:Protein Structure, Tertiary; D012886:Skull / Q000187:drug effects
chemical_list: D010446:Peptide Fragments; D019904:Polymethyl Methacrylate; D051550:I-kappa B Kinase