Suppression of NF‐κB‐induced chronic inflammation mitigates inflammatory osteolysis in the murine continuous polyethylene particle infusion model

Abstract

Wear particle‐associated bone loss (periprosthetic osteolysis) constrains the longevity of total joint arthroplasty (TJA). Wear particles induce a prolonged upregulation of nuclear factor kappa B (NF‐κB) signaling in macrophages and osteoclasts. Synthetic double‐stranded oligodeoxynucleotides (ODNs) can prevent the binding of NF‐κB to the promoter regions of targeted genes and inhibit genetic activation. We tested the hypothesis that polyethylene‐particle induced chronic inflammatory bone loss could be suppressed by local delivery of NF‐κB decoy ODNs in murine in vivo model. Polyethylene particles were continuously infused into the medullary cavity of the distal femur for 6 weeks to induce chronic inflammation, and micro‐computational tomography and immunohistochemical analysis were performed. Particle‐induced chronic inflammation resulted in lower BMD values, an increase in osteoclastogenesis and nuclear translocation of p65, a prolonged M1 pro‐inflammatory macrophage phenotype, and a decrease of M2 anti‐inflammatory macrophage phenotype. Delayed timing of local infusion of NF‐κB decoy ODN for the last 3 weeks reversed polyethylene‐particle associated chronic inflammatory bone loss and facilitated bone healing. This study demonstrated that polyethylene‐particle associated chronic inflammatory osteolysis can be effectively modulated via interference with the NF‐κB pathway; this minimally invasive intervention could potentially be an efficacious therapeutic strategy for periprosthetic osteolysis after TJA.

Mesenchymal Stem Cells and NF-κB Sensing Interleukin-4 Over-Expressing Mesenchymal Stem Cells Are Equally Effective in Mitigating Particle-Associated Chronic Inflammatory Bone Loss in Mice

“…The increased pro-inflammatory M1 macrophage proportion and the decreased anti-inflammatory M2 macrophage proportion caused by cPE over a 3-week period was subsequently reduced by the local injection of MSCs and NF-κB sensing IL-4 over-expressing MSCs at harvest 3 weeks later. The increased TRAP positive osteoclast-like cell number, the lower ALP positive osteoblast-like area and BMD trend in the presence of cPE infusion further confirmed that the cPE could induce bone loss ( Lin et al, 2016 , 2017a ; Pajarinen et al, 2017 ; Utsunomiya et al, 2021a , b ). The injection of MSCs and NF-κB sensing IL-4 over-expressing MSCs reversed these findings in part.…”

“…is still a major an unsolved problem. We have demonstrated that local delivery of contaminated polyethylene particles (cPE) can induce acute or chronic inflammation and polarize macrophages to a pro-inflammatory M1 rather than an anti-inflammatory M2 macrophage phenotype in different in vitro and in vivo models ( Utsunomiya et al, 2021a , b ). Macrophages are the characteristic cell type involved in chronic inflammation ( Allison et al, 1978 ; Maruyama et al, 2020 ); furthermore modulation of macrophage phenotype at an appropriate time can optimize osteogenic differentiation of MSCs ( Lin et al, 2019 ) and the enhancement of the bone regeneration ( Chow et al, 2019 ; Niu et al, 2021 ).…”

“…Nuclear factor kappa-light-chain- enhancer of activated B cells (NF-κB) is the key transcription factor associated with chronic inflammation and osteolysis ( Xu et al, 2009 ; Abu-Amer, 2013 ; Zuo et al, 2018 ). Previous studies have shown that suppression of NF-κB by its decoy oligodeoxynucleotides (ODNs) could enhance osteogenesis in MSCs exposed to polyethylene particles in vitro ( Lin et al, 2015 ) and mitigate the in vivo particle induced chronic inflammatory osteolysis ( Lin et al, 2016 , 2017a ; Utsunomiya et al, 2021b ). In the current study, NF-κB sensing IL-4 secreting MSCs produced IL-4 when the NF-κB pathway was activated by inflammatory signals; IL-4 production ceased when the inflammatory activation signal was withdrawn ( Lin et al, 2017b ).…”

Titanium Wear Particles Exacerbate S. epidermidis-Induced Implant-Related Osteolysis and Decrease Efficacy of Antibiotic Therapy

“…The identification of crucial signaling pathways involved in WP-induced pro-inflammatory responses and osteolysis therefore raises the possibility that pharmacological modulation of these pathways could prevent detrimental responses to WPs in patients. A variety of drugs have displayed efficacy in preventing osteolytic responses to WPs in vivo, particularly anti-resorptive agents targeting osteoclasts, such as bisphosphonates and osteoprotegerin (OPG) [36,37], and agents targeting pro-inflammatory signaling such as IL-1β [43] or NFκB activation [48], although these were assessed in the absence of a bacterial infection. Indeed, we have previously assessed the efficacy of the bisphosphonate zoledronic acid [26] and the non-steroid anti-inflammatory drug carprofen [30] for affecting osteolytic responses to S. epidermidis infection, but found both drugs to diminish antibiotic efficacy.…”

Sex Differences in Mesenchymal Stem Cell Therapy With Gelatin-Based Microribbon Hydrogels in a Murine Long Bone Critical-Size Defect Model

“…Both lower limbs from each animal were collected. µCT scans were performed using a TriFoileXplore CT 120 (TriFoil Imaging, Chatsworth, CA) with 50 μm resolution ( Ueno et al, 2020 ; Utsunomiya et al, 2021a ; Utsunomiya et al, 2021b ). In the left femur (the healthy side), a 3 × 3 × 2 mm rectangular region in the center of femur was scanned ( Figure 2A ).…”