title: NF-κB decoy oligodeoxynucleotide enhanced osteogenesis in mesenchymal stem cells exposed to polyethylene particle.
abstract: Excessive generation of wear particles after total joint replacement may lead to local inflammation and periprosthetic osteolysis. Modulation of the key transcription factor NF-κB in immune cells could potentially mitigate the osteolytic process. We previously showed that local delivery of ultrahigh-molecular-weight polyethylene (UHMWPE) particles recruited osteoprogenitor cells and reduced osteolysis. However, the biological effects of modulating the NF-κB signaling pathway on osteoprogenitor/mesenchymal stem cells (MSCs) remain unclear. Here we showed that decoy oligodeoxynucleotide (ODN) increased cell viability when primary murine MSCs were exposed to UHMWPE particles, but had no effects on cellular apoptosis. Decoy ODN increased transforming growth factor-beta 1 (TGF-β1) and osteoprotegerin (OPG) in MSCs exposed to UHMWPE particles. Mechanistic studies showed that decoy ODN upregulated OPG expression through a TGF-β1-dependent pathway. By measuring the alkaline phosphatase activity, osteocalcin levels, Runx2 and osteopontin expression, and performing a bone mineralization assay, we found that decoy ODN increased MSC osteogenic ability when the cells were exposed to UHMWPE particles. Furthermore, the cellular response to decoy ODN and UHMWPE particles with regard to cell phenotype, cell viability, and osteogenic ability was confirmed using primary human MSCs. Our results suggest that modulation of wear particle-induced inflammation by NF-κB decoy ODN had no adverse effects on MSCs and may potentially further mitigate periprosthetic osteolysis by protecting MSC viability and osteogenic ability.
authors.affiliation: 1 Department of Orthopaedic Surgery, Stanford University , Stanford, California.
authors.forename: Tzu-Hua
authors.initials: TH
authors.lastname: Lin
authors.forename: Taishi
authors.initials: T
authors.lastname: Sato
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Barcay
authors.forename: Heather
authors.initials: H
authors.lastname: Waters
authors.forename: Florence
authors.initials: F
authors.lastname: Loi
authors.forename: Ruth
authors.initials: R
authors.lastname: Zhang
authors.forename: Jukka
authors.initials: J
authors.lastname: Pajarinen
authors.forename: Kensuke
authors.initials: K
authors.lastname: Egashira
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Yao
authors.forename: Stuart B
authors.initials: SB
authors.lastname: Goodman
mesh_terms: D000328:Adult; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects; D008810:Mice, Inbred C57BL; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology* / Q000633:toxicity; D010012:Osteogenesis / Q000187:drug effects*; D053244:Osteoprotegerin / Q000378:metabolism; D011095:Polyethylenes / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D055815:Young Adult
chemical_list: C468119:NF-kappaB decoy; D009838:Oligodeoxyribonucleotides; D053244:Osteoprotegerin; D011095:Polyethylenes; D053773:Transforming Growth Factor beta1; C111601:ultra-high molecular weight polyethylene