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The effect of 800CW-pRIS intra-oral injection on osteonecrosis and gingival inflammation around socket in mice pretreated with ZOL a Distribution of 800CW-pRIS after intra-oral injection examined by IVIS and the corresponding micro-CT image. An intense 800CW signal is observed in the direction of injectant (yellow arrow) from the injection site and a weaker signal is seen in the peripheral zone (red arrows). The mesial section (M) has relatively less signal intensity compared to the distal section (D). b Percent area of osteonecrosis over the occlusal half of maxillary alveolar bone measured in the medial and distal sections (n = 8 per group). c Histological cross-sections of mesial and distal tooth extraction area with osteonecrosis (white dotted line: Nec) and inflammation (Inf and black arrows). The osteonecrosis area was normalized by the occlusal half of maxillary bone indicated by blue line. d Inflammation index (0–3) was evaluated by three blinded examiners. The graphs present the mean and standard deviation (n = 8 per group). Student’s t test was used. *p < 0.05; **p < 0.01. Source data: Supplementary Data 1, Fig. 5b, d.
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Background
Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a rare but serious side effect of nitrogen-containing bisphosphonate drugs (N-BPs) frequently prescribed to reduce skeletal-related events in bone malignancies and osteoporosis. BRONJ is associated with abnormal oral wound healing after dentoalveolar surgery and tooth extraction....
Citations
... We have developed a method to apply chemical therapeutic agents topically to the mouse maxillary tissue (Okawa et al., 2022a;Okawa et al., 2022b). We used the MTA model to apply oral microbial components ) (PMCID: PMC9474870; DOI: 10.1038/s42003-022-03896-7). This study used the MTA model using 1 µg/ml unmethylated CpG oligonucleotide (CpG ODN: InvivoGen, San Diego, CA) or P. gingivalis lipopolysaccharide (LPS: InvivoGen). ...
Periodontitis, one of the most common non-communicable diseases, is characterized by chronic oral inflammation and uncontrolled tooth supporting alveolar bone resorption. Its underlying mechanism to initiate aberrant oral barrier immunity has yet to be delineated. Here, we report a unique fibroblast subpopulation a ctivated to g uide oral inflammation (AG fibroblasts) identified in a single-cell RNA sequencing gingival cell atlas constructed from the mouse periodontitis models. AG fibroblasts localized beneath the gingival epithelium and in the cervical periodontal ligament responded to the ligature placement and to the discrete topical application of Toll-like receptor stimulants to mouse maxillary tissue. The upregulated chemokines and ligands of AG fibroblasts linked to the putative receptors of neutrophils in the early stages of periodontitis. In the established chronic inflammation, neutrophils, together with AG fibroblasts, appeared to induce type 3 innate lymphoid cells (ILC3s) that were the primary source of interleukin-17 cytokines. The comparative analysis of Rag2 -/- and Rag2 -/- Il2rg-/- mice suggested that ILC3 contributed to the cervical alveolar bone resorption interfacing the gingival inflammation. We propose the AG fibroblast–neutrophil–ILC3 axis as a previously unrecognized mechanism which could be involved in the complex interplay between oral barrier immune cells contributing to pathological inflammation in periodontitis.
... We have developed a method to apply chemical therapeutic agents topically to the mouse maxillary tissue (Okawa et al., 2022a;Okawa et al., 2022b). We used the MTA model to apply oral microbial components ) (PMCID: PMC9474870; DOI: 10.1038/s42003-022-03896-7). This study used the MTA model using 1 µg/ml unmethylated CpG oligonucleotide (CpG ODN: InvivoGen, San Diego, CA) or P. gingivalis lipopolysaccharide (LPS: InvivoGen). ...
Chronic cardiovascular and metabolic diseases have been linked with oral inflammation in the tooth-supporting gingiva. Therefore, elucidating the mechanisms underlying development of gingival inflammation may hold critical insight into the pathogenesis of these debilitating non-communicable diseases. Here, we report a unique fibroblast subpopulation activated to guide oral inflammation (AG fibroblasts), identified in a single-cell RNA sequencing-based gingival cell atlas constructed from the mouse ligature-induced periodontitis model. Collagen-XIV-positive AG fibroblasts localized beneath gingival epithelium express chemokine ligands and Toll-like receptor-related molecules upon ligature placement, which were linked to receptors expressed by neutrophils and lymphocytes, including innate lymphoid cells (ILCs). We further identify ILCs as the primary source of proinflammatory interleukin-17 cytokines and show that cervical alveolar bone resorption is absent in Rag2-/-γc-/-, but not Rag2-/-, mice suggesting ILC3s mediate the human periodontitis-like phenotype. We therefore propose AG fibroblasts function as a previously unrecognized surveillant to orchestrate chronic gingival inflammation in periodontitis.
... On the other hand, surgical treatments such as marginal or segmental resection of the jaw have been reported as viable options with high success rates for all stages of the disease [9,10]. Basic studies regarding treatment of ARONJ have reported the potential efficacy of disturbance of HMGB1/RAGE signaling [11], administration of inactive N-BP [12], geranylgeraniol (GGOH) [13,14], tetrahedral framework nucleic acid carrying angiogenic peptide [15], and hyperbaric oxygen therapy [16], although these treatments have not yet been shown to be effective in clinical settings. Although the precise mechanism underlying the pathogenesis of ARONJ is still unclear, the suppression of bone remodeling caused by disturbance of osteoclast activation [17] by BPs is thought to be one of the causes of osteonecrosis of the jaw. ...
... In addition, the specific mechanism by which healing is impaired is unknown, and it is not yet clear which cells are mobilized and involved in healing the scar after tooth extraction. Neovascularization has been reported to be an important factor in the pathogenesis of ARONJ [23,12]. A recent study reported that osteogenesis of extraction sockets and osteointegration of dental implants involve nearby bone marrow-derived cells expressing Gli-1 [24]. ...
Objective:
To explore the involvement of bone marrow cells and angiogenesis in the pathogenesis of antiresorptive agent-related osteonecrosis of the jaw (ARONJ).
Methods:
We performed micro-computed tomography (CT) and histological analyses in an ARONJ mouse model generated using bisphosphonate (BP) and cyclophosphamide (CY).
Results:
Micro-CT analysis showed that BP and CY inhibited osteoneogenesis in the extraction socket. Histological analysis at 3 days after tooth extraction showed inhibition of vascular endothelial cell and mesenchymal stem cell mobilization into the extraction socket. When neovascularization of the extraction fossa was observed from as early as 1 day after extraction, it occurred predominantly in the area adjacent to the extraction fossa and close to the bone marrow cavity. In addition, the extraction fossa communicated with the adjacent bone marrow via the vasculature. Histological evaluation of the alveolar bone marrow around the extraction socket showed a decrease in bone marrow cells in the BP + CY group.
Conclusion:
Both inhibition of angiogenesis and suppression of bone marrow cell mobilization are involved in the pathogenesis of ARONJ.
Periodontitis, one of the most common non-communicable diseases, is characterized by chronic oral inflammation and uncontrolled tooth supporting alveolar bone resorption. Its underlying mechanism to initiate aberrant oral barrier immunity has yet to be delineated. Here, we report a unique fibroblast subpopulation activated to guide oral inflammation (AG fibroblasts) identified in a single-cell RNA sequencing gingival cell atlas constructed from the mouse periodontitis models. AG fibroblasts localized beneath the gingival epithelium and in the cervical periodontal ligament responded to the ligature placement and to the discrete application of Toll-like receptor stimulants to mouse maxillary tissue. The upregulated chemokines and ligands of AG fibroblasts linked to the putative receptors of neutrophils in the early stages of periodontitis. In the established chronic inflammation, neutrophils together with AG fibroblasts appeared to induce type 3 innate lymphoid cells (ILC3s) that were the primary source of interleukin-17 cytokines. The comparative analysis of Rag2-/- and Rag2γc-/-mice suggested that ILC3 contributed to the cervical alveolar bone resorption interfacing the gingival inflammation. We propose that AG fibroblasts function as a previously unrecognized surveillant to initiate gingival inflammation leading to periodontitis through the AG fibroblast-neutrophil-ILC3 axis.
Chronic cardiovascular and metabolic diseases have been linked with oral inflammation in the tooth-supporting gingiva. Therefore, elucidating the mechanisms underlying development of gingival inflammation may hold critical insight into the pathogenesis of these debilitating non-communicable diseases. Here, we report a unique fibroblast subpopulation a ctivated to g uide oral inflammation (AG fibroblasts), identified in a single-cell RNA sequencing-based gingival cell atlas constructed from the mouse ligature-induced periodontitis model. Collagen-XIV-positive AG fibroblasts localized beneath gingival epithelium express chemokine ligands and Toll-like receptor-related molecules upon ligature placement, which were linked to receptors expressed by neutrophils and lymphocytes, including innate lymphoid cells (ILCs). We further identify ILCs as the primary source of proinflammatory interleukin-17 cytokines and show that cervical alveolar bone resorption is absent in Rag2 -/- γc -/- , but not Rag2 -/- , mice suggesting ILC3s mediate the human periodontitis-like phenotype. We therefore propose AG fibroblasts function as a previously unrecognized surveillant to orchestrate chronic gingival inflammation in periodontitis.
