NF-kappa B decoy oligodeoxynucleotide mitigates wear particle-associated bone loss in the murine continuous infusion model

Abstract

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-kappa B 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-kappa B 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 4 weeks. Particle-induced bone loss was evaluated by IICT, 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-kappa B decoy ODN reversed or further increased the bone mineral density in the femur (3-6 mm from the distal end) exposed to particles alone or particles plus LPS. NF-kappa B 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-kappa B activity via local delivery of decoy ODN has great potential to mitigate wear particle -induced osteolysis.