title: Suppression of wear-particle-induced pro-inflammatory cytokine and chemokine production in macrophages via NF-κB decoy oligodeoxynucleotide: a preliminary report.
abstract: Total joint replacement (TJR) is very cost-effective surgery for end-stage arthritis. One important goal is to decrease the revision rate, mainly because TJR has been extended to younger patients. Continuous production of ultra-high molecular weight polyethylene (UHMWPE) wear particles induces macrophage infiltration and chronic inflammation, which can lead to periprosthetic osteolysis. Targeting individual pro-inflammatory cytokines directly has not reversed the osteolytic process in clinical trials, owing to compensatory up-regulation of other pro-inflammatory factors. It is hypothesized that targeting the important transcription factor NF-κB could mitigate the inflammatory response to wear particles, potentially diminishing osteolysis. In the current study, NF-κB activity in mouse RAW 264.7 and human THP1 macrophage cell lines, as well as primary mouse and human macrophages, was suppressed via competitive binding with double strand decoy oligodeoxynucleotide (ODN) containing an NF-κB binding element. It was found that macrophage exposure to UHMWPE particles induced multiple pro-inflammatory cytokine and chemokine expression, including TNF-α, MCP1, MIP1α and others. Importantly, the decoy ODN significantly suppressed the induced cytokine and chemokine expression in both murine and human macrophages, and resulted in suppression of macrophage recruitment. The strategic use of decoy NF-κB ODN, delivered locally, could potentially diminish particle-induced periprosthetic osteolysis.
authors.affiliation: Department of Orthopaedic Surgery, Stanford University School of Medicine, 450 Broadway Street, Redwood City, CA 94063, USA.
authors.forename: Tzu-Hua
authors.initials: TH
authors.lastname: Lin
authors.affiliation: Department of Orthopaedic Surgery, Stanford University School of Medicine, 450 Broadway Street, Redwood City, CA 94063, USA.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Yao
authors.affiliation: Department of Orthopaedic Surgery, Stanford University School of Medicine, 450 Broadway Street, Redwood City, CA 94063, USA.
authors.forename: Taishi
authors.initials: T
authors.lastname: Sato
authors.affiliation: Department of Orthopaedic Surgery, Stanford University School of Medicine, 450 Broadway Street, Redwood City, CA 94063, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Keeney
authors.affiliation: Department of Orthopaedic Surgery, Stanford University School of Medicine, 450 Broadway Street, Redwood City, CA 94063, USA.
authors.forename: Chenguang
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Orthopaedic Surgery, Stanford University School of Medicine, 450 Broadway Street, Redwood City, CA 94063, USA.
authors.forename: Jukka
authors.initials: J
authors.lastname: Pajarinen
authors.affiliation: Department of Orthopaedic Surgery, Stanford University School of Medicine, 450 Broadway Street, Redwood City, CA 94063, USA; Department of Bioengineering, Stanford University, Stanford, CA, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.affiliation: Department of Cardiovascular Research, Development, and Translational Medicine, Kyushu University, Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Egashira
authors.affiliation: Department of Orthopaedic Surgery, Stanford University School of Medicine, 450 Broadway Street, Redwood City, CA 94063, USA; Department of Bioengineering, Stanford University, Stanford, CA, USA. Electronic address: goodbone@stanford.edu.
authors.forename: Stuart B
authors.initials: SB
authors.lastname: Goodman
mesh_terms: D000818:Animals; D002460:Cell Line; D018925:Chemokines / Q000276:immunology*; D016207:Cytokines / Q000276:immunology*; D015536:Down-Regulation / Q000187:drug effects; D020868:Gene Silencing; D006801:Humans; D007155:Immunologic Factors / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D009838:Oligodeoxyribonucleotides / Q000235:genetics / Q000494:pharmacology*; D010865:Pilot Projects; D011095:Polyethylenes / Q000009:adverse effects*
chemical_list: D018925:Chemokines; D016207:Cytokines; D007155:Immunologic Factors; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D011095:Polyethylenes; C111601:ultra-high molecular weight polyethylene
keywords: Macrophage; NF-κB decoy oligodeoxynucleotide; Periprosthetic osteolysis; Wear particles