NF-κB 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-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 4 weeks. 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.

NF-κB as a Therapeutic Target in Inflammatory-Associated Bone Diseases

“…The proinflammatory cytokines including TNF-α and IL-1β further activate NF-κB in macrophages as a positive regulatory loop during the chronic inflammation, leading to OC activation, and osteolytic processes (Lin, Pajarinen, et al, 2016; Lin, Tamaki, et al, 2014). Inhibition of NF-κB activity suppresses PMMA and UHMWPE wear particle induced OC activation in vitro and in vivo, suggesting the therapeutic potential of targeting NF-κB pathway in the particle disease (Clohisy, Hirayama, Frazier, Han, & Abu-Amer, 2004; Lin, Pajarinen, et al, 2016). …”

“…Alternatively, NF-κB decoy oligonucleotides (ODN) specifically compete for binding of NF-κB dimers to their DNA targets, and could simultaneously inhibit both canonical and noncanonical NF-κB pathway. It has been shown that NF-κB decoy ODN significantly suppress cyto-kine and chemokine expression in macrophages, especially in the setting of periprosthetic osteolysis (Lin, Pajarinen, et al, 2016; Lin et al, 2015; Lin, Yao, et al, 2014). Moreover, there are several NF-κB decoy ODN-based therapies that have entered clinical trials for dermatitis and psoriasis (Gilmore & Garbati, 2011).…”

PDGF-BB and IL-4 co-overexpression is a potential strategy to enhance mesenchymal stem cell-based bone regeneration

“…In order to monitor potential adverse effects of excessive IL-4 and PDGF-BB, an in vivo study is necessary. Further investigation will also be conducted using inflammation regulated GM MSCs such as with NF-kB sensing [5,18] In vivo confirmation of these findings of using GM MSCs in animal models of inflammatory bone loss [36] and nonunion in critical-size bone defects [37] are needed to confirm these in vitro observations.…”

Mesenchymal stem cells in the aseptic loosening of total joint replacements

“…Similarly, activation of Wnt/β‐catenin signaling with the compound Icariin was shown to rescue the Ti particle‐induced reduction in MSC‐mediated osteogenesis both in vitro and in vivo . Lin et al showed that blocking NF‐kB signaling with decoy ODN limited wear particle responses both in vitro and in vivo . Finally, Lee et al showed that AZD6244, a clinically relevant inhibitor of ERK pathway, attenuated Ti particle‐induced reduction in MSC function in vitro and in vivo .…”

“…104 Lin et al showed that blocking NF-kB signaling with decoy ODN limited wear particle responses both in vitro and in vivo. 86,129 Finally, Lee et al showed that AZD6244, a clinically relevant inhibitor of ERK pathway, attenuated Ti particle-induced reduction in MSC function in vitro and in vivo. 103 Although successful in cell cultures and animal models, the translational potential of these concepts remains to be determined.…”