Macrophage polarization in aseptic bone resorption around dental implants induced by Ti particles in a murine model

Abstract

Background and Objectives Titanium particles/ions detected in peri‐implant tissues have been considered as a potential etiologic factor for crestal bone loss around oral implants. However, the definite impact of titanium wear particles on the health of surrounding structures remains undetermined. The purpose of this study was to investigate the effects of titanium particles‐induced foreign body reaction on peri‐implant bone level and the related mechanism by using clodronate liposomes to deplete macrophages. Material and Methods Sprague Dawley rats with custom‐made titanium screw implanted in bilateral maxillary first molar area for 4 weeks to obtain osseointegration were randomly divided into four groups. Twenty microgram titanium particles were introduced into the peri‐implant tissue to induce aseptic foreign body reaction, and macrophages were depleted by the local injection of 100 μL clodronate liposome immediately and re‐injection every 3 days until the sacrifice of the rats (Ti + LipClod group). Titanium‐injected rats also treated with phosphate buffer solution (Ti + PBS) or empty liposome (Ti + Lip) as well as rats injected with PBS alone (Control) were included as controls. Eight weeks later, animals were sacrificed and samples containing implants were collected. Half of the samples were analyzed radiologically to measure bone level change, and macrophage markers (CD68, CCR7, CD163) was also characterized by immunofluorescence to evaluate macrophage number, density, and phenotype distribution (CCR7+M1/CD163+M2). The rest of the samples were used to determine the relative mRNA expression levels of TNF‐α, IL‐1β, IL‐6, and RANKL with real‐time PCR analysis. Results No obvious bacterial contamination was found in all titanium‐injected areas, and the implant survival rate was 100% with no implant loss. Compared with Ti + PBS and Ti + Lip group, macrophage density (1.64 ± 0.86%) infiltrated into peri‐implant tissue and bone loss (0.17 ± 0.03 mm) around implant decreased significantly in the Ti + LipClod group. Immunofluorescence analysis showed that more macrophage infiltrated into peri‐implant tissue in the Ti + PBS and Ti + Lip groups, predominantly with M1 phenotype. In contrast, the macrophage density was lower and M2 phenotype was dominant in the Control group, while macrophages density was significantly reduced and the M1 type macrophages were slightly more than M2 type in the Ti + LipClod group. Accordingly, TNF‐α, IL‐1β, IL6, and RANKL mRNA expression increased significantly in the Ti + PBS and Ti + Lip groups compared with Control and Ti + LipClod groups. Conclusions Titanium particles had a negative effect on peri‐implant tissue by activating macrophages which induced an M1 macrophage phenotype promoting local secretion of inflammatory cytokines. It was found that clodronate liposome treatment attenuated the severity of inflammation and bone loss by depletion of macrophages. Therefore, the present study revealed the marked impact of macrophage polarization with respect to peri‐implant bone loss caused...

Characterization of macrophages infiltrating peri‐implantitis lesions

“…The current literature on macrophage polarization does not have a clear consensus on markers to identify M1 polarization and M2 polarization, and emerging data suggest an increased complexity on the differentiation of macrophages dependent on environmental cues. Few studies proposed staining protocols for activated macrophages with iNOS (He et al, ; Tang, Zhao, Lei, Chen, & Zhang, ), CCR7 (Wang, Li, Feng, Cheng, & Li, ) for detecting M1 phenotypes, while others used CD206 (Viniegra et al, ) (Lee et al, ; Nawaz et al, ; C. Zhang et al, ) or CD163 (Ham et al, ; Wang et al, ) for M2 phenotypes. The presence of subtypes of macrophage polarization like M2a, M2b, M2c, and M2d also remains to be defined in periodontal diseases.…”

“…Nawaz et al, 2017;C. Zhang et al, 2017) or CD163 (Ham et al, 2017;Wang et al, 2019) ies will help to shed light on the macrophage signature and their potential contribution to the transition of peri-implant mucositis into peri-implantitis.…”

Bone loss around oral and orthopedic implants: An immunologically based condition

“…33 Having said this, antibiotics seem needed in oral implant as well as in joint replacement surgery during the initial phase of implantation to prevent impaired clinical results due to early infections. 33 Having said this, antibiotics seem needed in oral implant as well as in joint replacement surgery during the initial phase of implantation to prevent impaired clinical results due to early infections.…”

“…The presence of aseptic loosening was recently demonstrated in a study on oral implants placed in rats locally injected with titanium particles supporting the notion that immune reactions are behind marginal bone loss. 33 Having said this, antibiotics seem needed in oral implant as well as in joint replacement surgery during the initial phase of implantation to prevent impaired clinical results due to early infections. 16,34 With oral implants, one single preoperative dose of antibiotics was satisfactory to reach a significantly lower failure rate than using no antibiotics at all.…”

The USP14–NLRC5 pathway inhibits titanium particle–induced osteolysis in mice by suppressing NF-κB and PI3K/AKT activities

“…After exposed to different stimulation, the resting macrophages (M0) are capable of polarizing to two mainly specific phenotypes with "classically" and "alternatively" activated macrophages, representing proinflammatory M1 and antiinflammatory M2 macrophages [9]. Wear particles had been proved to activate the macrophages which induced an M1 macrophage phenotype promoting local secretion of inflammatory cytokines [10]. M1 macrophage polarization is associated with high levels of these cytokines so it is tempting to ascribe M1 macrophages as cells promoting osteoclastogenesis whilst the M2 macrophages would inhibit this process [11].…”