NF-κB decoy oligodeoxynucleotide mitigates wear particle-associated bone loss in the murine continuous infusion model.
Total joint replacement is a cost-effective surgical procedure for patients with end-stage arthritis. Wear particle-induced chronic inflammation is associated with the development of periprosthetic osteolysis. Modulation of NF-κB signaling in macrophages, osteoclasts, and mesenchymal stem cells could potentially mitigate this disease. In the current study, we examined the effects of local delivery of decoy NF-κB oligo-deoxynucleotide (ODN) on wear particle-induced bone loss in a murine continuous femoral particle infusion model. Ultra-high molecular weight polyethylene particles (UHMWPE) with or without lipopolysaccharide (LPS) were infused via osmotic pumps into hollow titanium rods placed in the distal femur of mice for 4weeks. Particle-induced bone loss was evaluated by μCT, and immunohistochemical analysis of sections from the femur. Particle infusion alone resulted in reduced bone mineral density and trabecular bone volume fraction in the distal femur. The decoy ODN reversed the particle-associated bone volume fraction loss around the implant, irrespective of the presence of LPS. Particle-infusion with LPS increased bone mineral density in the distal femur compared with particle-infusion alone. NF-κB decoy ODN reversed or further increased the bone mineral density in the femur (3-6mm from the distal end) exposed to particles alone or particles plus LPS. NF-κB decoy ODN also inhibited macrophage infiltration and osteoclast number, but had no significant effects on osteoblast numbers in femurs exposed to wear particles and LPS. Our study suggests that targeting NF-κB activity via local delivery of decoy ODN has great potential to mitigate wear particle-induced osteolysis.



Total joint replacement is a cost-effective surgical procedure for patients with end-stage arthritis. Chronic inflammation is crucial for the development of wear particle-associated bone loss. Modulation of NF-κB signaling in macrophages (pro-inflammatory cells), osteoclasts (bone-resorbing cells), and osteoblasts (bone-forming cells) could potentially mitigate this disease. Here we demonstrated that local delivery of decoy NF-κB oligo-deoxynucleotide (ODN) mitigated ultra-high molecular weight polyethylene (UHMWPE) wear particle induced bone loss in a clinically relevant murine model. The protective effects of decoy ODN was associated with reduced macrophage infiltration and osteoclast activation, but had no significant effects on osteoblast numbers. Our study suggests that targeting NF-κB activity via local delivery of decoy ODN has great potential to mitigate wear particle-induced bone loss.
Department of Orthopaedic Surgery, Stanford University, Stanford, CA, USA.
Tzu-Hua
TH
Lin
Department of Orthopaedic Surgery, Stanford University, Stanford, CA, USA.
Jukka
J
Pajarinen
Department of Orthopaedic Surgery, Stanford University, Stanford, CA, USA.
Taishi
T
Sato
Department of Orthopaedic Surgery, Stanford University, Stanford, CA, USA.
Florence
F
Loi
Department of Orthopaedic Surgery, Stanford University, Stanford, CA, USA.
Changchun
C
Fan
Department of Orthopaedic Surgery, Stanford University, Stanford, CA, USA; Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, University of Chile-CONICYT, Santiago, Chile.
Luis A
LA
Córdova
Department of Orthopaedic Surgery, Stanford University, Stanford, CA, USA.
Akira
A
Nabeshima
Department of Orthopaedic Surgery, Stanford University, Stanford, CA, USA; Biomechanics and Bone & Joint Biomaterials Laboratory, UMR CNRS 7052, School of Medicine, Paris 7 University, Paris, France.
Emmanuel
E
Gibon
Department of Orthopaedic Surgery, Stanford University, Stanford, CA, USA.
Ruth
R
Zhang
Department of Orthopaedic Surgery, Stanford University, Stanford, CA, USA.
Zhenyu
Z
Yao
Department of Orthopaedic Surgery, Stanford University, Stanford, CA, USA; Department of Bioengineering, Stanford University, Stanford, CA, USA. Electronic address: goodbone@stanford.edu.
Stuart B
SB
Goodman
D000818:Animals; D015519:Bone Density / Q000187:drug effects; D001862:Bone Resorption / Q000188:drug therapy* / Q000473:pathology; D000071556:Cancellous Bone / Q000187:drug effects / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D018483:Diaphyses / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D005269:Femur / Q000187:drug effects / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology / Q000627:therapeutic use*; D010006:Osteoblasts / Q000187:drug effects / Q000473:pathology; D011095:Polyethylenes / Q000009:adverse effects*; D000067996:RAW 264.7 Cells
D008070:Lipopolysaccharides; C468119:NF-kappaB decoy; D009838:Oligodeoxyribonucleotides; D011095:Polyethylenes; C111601:ultra-high molecular weight polyethylene
Chronic inflammation; NF-κB decoy oligodeoxynucleotide; Periprosthetic osteolysis; Wear particles