Local effect of IL‐4 delivery on polyethylene particle induced osteolysis in the murine calvarium

Abstract

Wear particles generated with use of total joint replacements incite a chronic macrophage-mediated inflammatory reaction, which leads to implant failure. Macrophage activation may be polarized into two states, with an M1 proinflammatory state dominating an alternatively activated M2 anti-inflammatory state. We hypothesized that IL-4, an activator of M2 macrophages, could modulate polyethylene (PE) particle-induced osteolysis in an experimental murine model. Four animal groups included (a) calvarial saline injection with harvest at 14 days (b) single calvarial injection of PE particles subcutaneously (SC) without IL-4 (c) PE particles placed as in (b), then IL-4 given SC for 14 consecutive days and (d) PE particles as in (b) then IL-4 beginning 7 days after particle injection for 7 days. The calvarial bone volume to total tissue volume was measured using microCT and histomorphometry. Calvaria were cultured for 24 h to assess release of RANKL, OPG, TNF-α, and IL-1ra and isolation and identification of M1 and M2 specific proteins. MicroCT and histomorphometric analysis showed that bone loss was significantly decreased following IL-4 administration to PE treated calvaria for both 7 and 14 days. Western blot analysis showed an increased M1/M2 ratio in the PE treated calvaria, which decreased with addition of IL-4. Cytokine analysis showed that the RANKL/OPG ratio and TNF-α/IL-1ra ratio decreased in PE-treated calvaria following IL-4 addition for 14 days. IL-4 delivery mitigated PE particle-induced osteolysis through macrophage polarization. Modulation of macrophage polarization is a potential treatment strategy for wear particle induced periprosthetic osteolysis.

Probiotics protect mice from CoCrMo particles-induced osteolysis

“…As previously described, 6 each of the calvaria was placed into a well of a 12-well plate and cultured with 2 mL Dulbecco's Modified Eagle's Medium (DMEM; Thermo Fisher Scientific, Waltham, MA, USA) for 24 hours at 37°C with 5% CO 2 . The culture medium was collected and stored at −20°C for assay of receptor activator of nuclear factor (NF)-κB ligand (RANKL), osteoprotegerin (OPG), TNF-α, IL-6, IL-4 and IL-10.…”

“…The concept of macrophage polarization was recently considered to play a role in the pathological mechanism of aseptic loosening. 1,6,7 M1 proinflammatory macrophages were activated in response to wear debris dominating the M2 antiinflammatory response. M1 macrophages secrete primarily proinflammatory cytokines such as TNF-α, IL-6 and IL-1β, while M2 macrophages produce anti-inflammatory mediators such as IL-4, IL-10 and IL-13.…”

“…2,35 However, macrophages are the main cell type responsible for the expression of proinflammatory cytokines in vivo, and the changes in proinflammatory cytokines reflect the functional state of macrophages. 2,6,15,36 Rao et al adopted these indexes to identify the phenotypes of macrophages. 6 Second, the mechanism responsible for the change in macrophage phenotype induced by probiotics remains unclear.…”

Generation of anti-inflammatory macrophages for implants and regenerative medicine using self-standing release systems with a phenotype-fixing cytokine cocktail formulation

“…For this purpose, anti-inflammatory cytokines and their combinations can be loaded on thin adhesive coatings. For example, local immunomodulation using well recognized antiinflammatory factor IL4 alleviated biomaterial-induced osteolysis in mice [21]. Controlled release of IL4 from polyelectrolyte multilayer-based coatings and silk biomaterials was shown to promote differentiation of macrophages with anti-inflammatory M2 properties [16,22].…”

Are Biologic Treatments a Potential Approach to Wear- and Corrosion-related Problems?

“…Two approaches applied the antiinflammatory cytokine IL-4 alone or in combination with IL-13 to the site of particle addition [55]. Addition of IL-4 at the time of addition of particles in a subcutaneous model showed that bone thickness was improved and that TNF and RANKL expression was decreased [35]. In addition, the type of macrophage localized at the site of particle deposition was shifted to an M2 profile from an M1 profile.…”