Abnormal macrophage polarization impedes the healing of diabetes-associated tooth sockets

Shen, Xiang; Shen, Xin; Li, Bang; Zhu, Weiwen; Fu, Yu; Xu, Rongyao; Du, Yifei; Cheng, Jie; Jiang, Hongbing

doi:10.1016/j.bone.2020.115618

Cited by 24 publications

(16 citation statements)

References 48 publications

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“… 79 M1s triggered by BcHA could resolve possible bacterial invasion through acute proinflammatory activity and favorable M2 transition may help alleviating the innate immune response in time to prompt the prohealing response. 80 , 81 This transition could be facilitated with the BcHA-related increase in VEGF-A 82 and BMP-2 83 upregulation.…”

Section: Discussionmentioning

confidence: 99%

Versatile-in-All-Trades: Multifunctional Boron-Doped Calcium-Deficient Hydroxyapatite Directs Immunomodulation and Regeneration

Pazarçeviren

Akbaba

Evis

et al. 2022

ACS Biomater. Sci. Eng.

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Osseointegration of implants depends on several intertwined factors: osteogenesis, angiogenesis, and immunomodulation. Lately, novel reinforcements allowing faster bonding with osseous tissue have been explored intensively. In this study, we hypothesized the use of boron as a major multifunctional ion to confer versatility to calcium-deficient hydroxyapatite (cHA) synthesized by a wet precipitation/microwave reflux method. By synthesis of boron-doped calcium-deficient hydroxyapatite (BcHA), we expected to obtain an osteoimmunomodulatory and regenerative nanoreinforcement. BcHA was found to possess a pure HA phase, a greater surface area (66.41 m 2 /g, p = 0.028), and cumulative concentrations of Ca (207.87 ± 6.90 mg/mL, p < 0.001) and B (112.70 ± 11.79 mg/mL, p < 0.001) released in comparison to cHA. Osteogenic potential of BcHA was analyzed using human fetal osteoblasts. BcHA resulted in a drastic increase in the ALP activity (1.11 ± 0.11 mmol/gDNA·min, p < 0.001), biomineralization rate, and osteogenic gene expressions compared to cHA. BcHA angiogenic potential was investigated using human umbilical cord vein endothelial cells. Significantly, the highest VEGF-A release (1111.14 ± 87.82 in 4 h, p = 0.009) and angiogenic gene expressions were obtained for BcHA-treated samples. These samples were also observed to induce a more prominent and highly branched tube network. Finally, inflammatory and inflammasome responses toward BcHA were elucidated using human monocyte-derived macrophages differentiated from THP-1s. BcHA exhibited lower CAS-1 release (50.18 ± 5.52 μg/g DNA μg/gDNA) and higher IL-10 release (126.97 ± 15.05 μg/g DNA ) than cHA. In addition, BcHA treatment led to increased expression of regenerative genes such as VEGF-A, RANKL, and BMP-2. In vitro results demonstrated that BcHA has tremendous osteogenic, angiogenic, and immunomodulatory potential to be employed as a “versatile-in-all-trades” modality in various bone tissue engineering applications.

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Section: Discussionmentioning

confidence: 99%

Versatile-in-All-Trades: Multifunctional Boron-Doped Calcium-Deficient Hydroxyapatite Directs Immunomodulation and Regeneration

Pazarçeviren

Akbaba

Evis

et al. 2022

ACS Biomater. Sci. Eng.

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“…M1 macrophages were activated in the inflammatory stage of PD while M2 macrophages were enhanced in the healing stage 34,35 . In addition, the ratio of M1/M2 macrophages polarization is not only correlated with the stages of PD, 36 but also can serve as a regulatory target to change alveolar bone loss during PD 37,38 . Wu et al reported that alveolar bone resorption in murine PD can be mitigated by decreasing M1/M2 ratio with local injection of AKT inhibitor 35 .…”

Section: Discussionmentioning

confidence: 99%

“…34,35 In addition, the ratio of M1/M2 macrophages polarization is not only correlated with the stages of PD, 36 but also can serve as a regulatory target to change alveolar bone loss during PD. 37,38 Wu et al reported that alveolar bone resorption in murine PD can be mitigated by decreasing M1/M2 ratio with local injection of AKT inhibitor. 35 Also, reduction of M1/M2 ratio can help preserve alveolar bone in P.g-induced murine PD through gingiva injection of C-C motif chemokine ligand 2.…”

Section: Discussionmentioning

confidence: 99%

Unloading of occlusal force aggravates alveolar bone loss in periodontitis

Zhu

Zhang

et al. 2022

J of Periodontal Research

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Background and Objective: Periodontitis (PD), a chronic infectious inflammatory disease initiated by bacteria, is associated with several local contributing factors including occlusal trauma. Previous studies have found that the traumatic occlusal force could aggravate alveolar bone loss during PD. However, the effect of reduced occlusal force during PD remains unclear. This study aimed to explore the effect of occlusal force unloading on PD onset and progression and its underlying mechanism as an effort to provide restoration suggestions for PD patients with dentition defect in clinic.This study might also propose occlusal force unloading could be a new local contributing factor for PD. Materials and Methods: C57BL/6 mice were used to establish a PD model by the ligation of 5-0 silk around the mandibular left first molar (PD group) and an unloading experiment model by the extraction of their left maxillary first molar (EX group). The THP-1-derived macrophages were used to verify in vivo results. Results: Micro-CT scanning and H&E staining results consistently showed that PD + EX group experienced the most severe alveolar bone resorption as compared to PD group and control group. Further RNA-sequencing analysis suggested that occlusal force unloading significantly enhanced osteoclastic resorption, inhibited osteoblastic activity, and promotes M1 and M2 macrophages polarization. Immunofluorescence staining (IF) results showed that compared with the PD group, PD + EX group significantly increased the ratio of M1/M2 polarization. Similar results were observed by RT-qPCR and IF in vitro: removal of compressive force led to an increased ratio of M1/ M2 polarization in LPS-stimulated THP-1-derived macrophages.Conclusions: Our study demonstrated that occlusal force unloading aggravates bone resorption by increasing the ratio of M1/M2 macrophages polarization during PD, suggesting a previously unknown local contributing factor for PD, and providing a novel insight for dentists to restore missing teeth as an effort to maintain remaining dentition.

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“…Similarly, systemic application of rosiglitazone skewed macrophage polarization toward M2 phenotype, protecting against bone resorption during inflammatory process and promoting bone regeneration during healing process of periodontitis 51 . In diabetic condition, macrophages skewed toward M1 macrophages, which was responsible for the delay of alveolar bone healing after tooth extraction, and macrophage repolarization toward M2 by biomaterial incorporating IL‐4 could improve the healing 58 …”

Section: Discussionmentioning

confidence: 99%

Hyperglycemia modulates M1/M2 macrophage polarization via reactive oxygen species overproduction in ligature‐induced periodontitis

Zhang

Yang

2021

J of Periodontal Research

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Background and objective Periodontitis in diabetic patients is characterized by enhanced inflammation and aggravated tissue damage in comparison with that in non‐diabetic counterparts. The progression of periodontal damage under diabetic condition can be partly ascribed to hyperglycemia‐induced disturbance between immune activation and inflammation resolution, where macrophages are capable of participating given their plasticity in response to different stimuli. Herein, we aimed to investigate the changes of macrophage polarization in periodontitis under diabetic condition and the underlying mechanism. Materials and Methods Type‐1 diabetes was induced by the injection of streptozotocin (STZ, 60 mg/kg) in Sprague‐Dawley rats. Rats in N‐acetyl cysteine (NAC)‐treated groups received NAC dissolved in drinking water (200 mg/kg/day). Experimental periodontitis was induced by ligating 3–0 silk around left maxillary second molars for 4 weeks. Alveolar bone destruction was tested by micro‐computed tomography and tartrate‐resistant acid phosphatase (TRAP) staining. M1/M2 macrophage polarization in periodontal tissue was detected by immunohistochemistry staining. RAW264.7 were cultured in normal glucose (5.5 mM) or high glucose environment (25 mM) with or without NAC (8 mmol/L). LPS (100 ng/ml) and IL‐4 (20 ng/ml) were used to induce M1 macrophages and M2 macrophages, respectively. M1/M2 macrophage polarization was detected by qRT‐PCR, immunofluorescent staining, and flow cytometry. Reactive oxygen species (ROS) accumulation was detected by fluorogenic probes. RANKL (100 ng/ml) were applied to induce osteoclastogenic differentiation of RAW264.7, and osteoclast formation was examined by TRAP staining. Results Rats with diabetes displayed enhanced macrophages infiltration and M1 macrophage polarization in periodontal lesions compared with vehicle‐treated rats. Under LPS or IL‐4 stimulation, high glucose culture of RAW264.7 elevated ROS level and increased the expression of M1 macrophage markers (iNOS, TNF‐α, and IL‐6) whereas decreased the expression of M2 macrophage markers (Arg‐1 and CD206). Supernatants of high glucose‐treated M1/M2 macrophages enhanced osteoclast formation compared to normal glucose‐cultured cells. Decreasing ROS level via NAC partially reversed the effect of high glucose on M1/M2 macrophage polarization. Meanwhile, daily intake of NAC in rodent models inhibited M1 macrophage polarization, which subsequently ameliorated alveolar bone loss and decreased osteoclast numbers in periodontitis in diabetic rats. Conclusion These findings demonstrated that hyperglycemia could polarize macrophage toward M1 macrophages via overproducing ROS under inflammatory condition, which might take responsibility for aggravated periodontal damage in periodontitis under diabetic condition. Inhibiting M1 macrophages and restoring M2 macrophages by ROS scavenger is hopefully a potential adjunct treatment strategy for diabetic periodontitis.

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Abnormal macrophage polarization impedes the healing of diabetes-associated tooth sockets

Cited by 24 publications

References 48 publications

Versatile-in-All-Trades: Multifunctional Boron-Doped Calcium-Deficient Hydroxyapatite Directs Immunomodulation and Regeneration

Versatile-in-All-Trades: Multifunctional Boron-Doped Calcium-Deficient Hydroxyapatite Directs Immunomodulation and Regeneration

Unloading of occlusal force aggravates alveolar bone loss in periodontitis

Hyperglycemia modulates M1/M2 macrophage polarization via reactive oxygen species overproduction in ligature‐induced periodontitis

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