Pub Date : 2025-10-18DOI: 10.1177/00220345251378094
S Yoshida,E O Maruyama,W Hsu,G T-J Huang,T Maruyama
Dental pulp is crucial for maintaining tooth vitality and function. Vital pulp provides defense mechanisms, sensory function, and tooth structural integrity. The presence of dental pulp stem cells (DPSCs) plays a role in the regeneration of damaged pulp and dentin. In immature teeth, the apical papilla at the apex harbors stem cells that are involved in root formation and maturation. Although stem cells isolated from the pulp and apical papilla have shown regenerative capacities, the in situ process of their involvement in pulp and dentin regeneration in response to injury is still unclear. Here, using single-cell transcriptomics and lineage tracing techniques, we identified the presence of endogenous Axin2+ DPSCs localized at the apex of mouse molars. The single-cell profiling identified 6 subpopulations of molar pulp tissue, including odontoblasts, pulp cells, and DPSCs. Lineage tracing analysis revealed that Axin2+ DPSCs gradually expand at the root apex and differentiate into pulp cells within the canal, contributing to pulp tissue formation in the pulp chamber and eventually maturing into odontoblasts over a period of at least 9 months. Upon pulp exposure or injury, the DPSCs rapidly proliferate and facilitate pulp healing and reparative dentin formation. Furthermore, the regenerative potential of the isolated DPSCs was demonstrated through their transplantation into the kidney capsule, leading to the successful formation of ectopic pulp tissue and reparative dentin. Identifying novel DPSCs at the apex provides new insights into pulp biology and establishes a foundation for regenerative endodontic therapies, leading to the deciphering of underlying mechanisms and development of new therapeutic strategies.
{"title":"Identification of Apically Localized Endogenous Dental Pulp Stem Cells.","authors":"S Yoshida,E O Maruyama,W Hsu,G T-J Huang,T Maruyama","doi":"10.1177/00220345251378094","DOIUrl":"https://doi.org/10.1177/00220345251378094","url":null,"abstract":"Dental pulp is crucial for maintaining tooth vitality and function. Vital pulp provides defense mechanisms, sensory function, and tooth structural integrity. The presence of dental pulp stem cells (DPSCs) plays a role in the regeneration of damaged pulp and dentin. In immature teeth, the apical papilla at the apex harbors stem cells that are involved in root formation and maturation. Although stem cells isolated from the pulp and apical papilla have shown regenerative capacities, the in situ process of their involvement in pulp and dentin regeneration in response to injury is still unclear. Here, using single-cell transcriptomics and lineage tracing techniques, we identified the presence of endogenous Axin2+ DPSCs localized at the apex of mouse molars. The single-cell profiling identified 6 subpopulations of molar pulp tissue, including odontoblasts, pulp cells, and DPSCs. Lineage tracing analysis revealed that Axin2+ DPSCs gradually expand at the root apex and differentiate into pulp cells within the canal, contributing to pulp tissue formation in the pulp chamber and eventually maturing into odontoblasts over a period of at least 9 months. Upon pulp exposure or injury, the DPSCs rapidly proliferate and facilitate pulp healing and reparative dentin formation. Furthermore, the regenerative potential of the isolated DPSCs was demonstrated through their transplantation into the kidney capsule, leading to the successful formation of ectopic pulp tissue and reparative dentin. Identifying novel DPSCs at the apex provides new insights into pulp biology and establishes a foundation for regenerative endodontic therapies, leading to the deciphering of underlying mechanisms and development of new therapeutic strategies.","PeriodicalId":15596,"journal":{"name":"Journal of Dental Research","volume":"39 1","pages":"220345251378094"},"PeriodicalIF":7.6,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145311198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-18DOI: 10.1177/00220345251365596
B. Bay, K. Borof, B. Cheng, B. Lieske, L. Tilemann, L. Wees, B.-C. Zyriax, C.-A. Behrendt, G. Thomalla, S. Blankenberg, T. Beikler, R. Twerenbold, F.J. Brunner, G. Aarabi
Periodontitis (PD) as chronic inflammatory disease has been linked with the development of atherosclerotic cardiovascular disease (ASCVD). However, there is a lack of data with regard to the association of PD across the extent of ASCVD and clinical outcomes, which we sought to investigate. Randomly recruited participants from the Hamburg City Health Study were included. The cohort was grouped according to severity of ASCVD at baseline: no ASCVD, monovascular disease (MonoVD), and polyvascular disease (PolyVD). PD was assessed categorically by degree of severity and continuously by clinical attachment loss. Logistic regression models were implemented to investigate the association of PD with prevalent ASCVD subtypes. Kaplan-Meier curves and Cox regression analyses were computed to investigate the associations of clinical attachment loss with major adverse cardiovascular events (composite of all-cause death, myocardial infarction, ischemic stroke, any unplanned coronary revascularization, and new diagnosis of cerebrovascular disease or peripheral arterial disease) across the extent of ASCVD. Across the 6,209 individuals included ( n = 3,049, no ASCVD; n = 2,283, MonoVD; n = 877, PolyVD), participants with PolyVD had the highest rates of severe PD. On binary logistic regression analysis, severe PD was independently associated with MonoVD (odds ratio, 1.32; 95% CI, 1.09 to 1.61; P = 0.005) and PolyVD (odds ratio, 1.57; 95% CI, 1.16 to 2.13; P = 0.004). During a median follow-up of 5.5 y (95% CI, 5.3 to 5.6), a trend toward higher major adverse cardiovascular event rates was observed in individuals with ASCVD and the highest clinical attachment loss tertile. However, no independent association of mean clinical attachment loss with adverse events was noted. PD is highly prevalent in patients with more extensive ASCVD, and severe PD is associated with MonoVD and PolyVD. However, no association of PD with major adverse cardiovascular events was noted. These data suggest that PD may be associated with cardiovascular risk in the population.
牙周炎（PD）作为慢性炎症性疾病与动脉粥样硬化性心血管疾病（ASCVD）的发展有关。然而，缺乏关于PD与ASCVD程度和临床结果之间关系的数据，我们试图对此进行调查。从汉堡城市健康研究中随机招募的参与者包括在内。根据基线时ASCVD的严重程度分组：无ASCVD、单血管疾病（MonoVD）和多血管疾病（PolyVD）。PD以严重程度分类评估，并以临床依恋丧失持续评估。采用Logistic回归模型研究PD与流行ASCVD亚型的关系。通过Kaplan-Meier曲线和Cox回归分析，研究临床依恋丧失与ASCVD范围内主要不良心血管事件（包括全因死亡、心肌梗死、缺血性卒中、任何计划外冠状动脉血运重建术和脑血管疾病或外周动脉疾病的新诊断）的关联。在纳入的6209人中（n = 3049人，无ASCVD； n = 2283人，单纯性心血管疾病；n = 877人，多发性心血管疾病），多发性心血管疾病的参与者患严重PD的比例最高。在二元logistic回归分析中，重度PD与MonoVD（优势比，1.32;95% CI, 1.09 ~ 1.61; P = 0.005）和PolyVD（优势比，1.57;95% CI, 1.16 ~ 2.13; P = 0.004）独立相关。在中位随访时间为5.5年（95% CI, 5.3 - 5.6）期间，ASCVD患者和临床依附丧失发生率最高的患者有较高的主要不良心血管事件发生率的趋势。然而，没有注意到平均临床依恋丧失与不良事件的独立关联。PD在更广泛的ASCVD患者中非常普遍，严重的PD与单纯性和多重性vd相关。然而，PD与主要不良心血管事件没有关联。这些数据表明，PD可能与人群中的心血管风险有关。
{"title":"Periodontal Health and Outcome of Atherosclerotic Disease in the Hamburg City Health Study","authors":"B. Bay, K. Borof, B. Cheng, B. Lieske, L. Tilemann, L. Wees, B.-C. Zyriax, C.-A. Behrendt, G. Thomalla, S. Blankenberg, T. Beikler, R. Twerenbold, F.J. Brunner, G. Aarabi","doi":"10.1177/00220345251365596","DOIUrl":"https://doi.org/10.1177/00220345251365596","url":null,"abstract":"Periodontitis (PD) as chronic inflammatory disease has been linked with the development of atherosclerotic cardiovascular disease (ASCVD). However, there is a lack of data with regard to the association of PD across the extent of ASCVD and clinical outcomes, which we sought to investigate. Randomly recruited participants from the Hamburg City Health Study were included. The cohort was grouped according to severity of ASCVD at baseline: no ASCVD, monovascular disease (MonoVD), and polyvascular disease (PolyVD). PD was assessed categorically by degree of severity and continuously by clinical attachment loss. Logistic regression models were implemented to investigate the association of PD with prevalent ASCVD subtypes. Kaplan-Meier curves and Cox regression analyses were computed to investigate the associations of clinical attachment loss with major adverse cardiovascular events (composite of all-cause death, myocardial infarction, ischemic stroke, any unplanned coronary revascularization, and new diagnosis of cerebrovascular disease or peripheral arterial disease) across the extent of ASCVD. Across the 6,209 individuals included ( <jats:italic toggle=\"yes\">n</jats:italic> = 3,049, no ASCVD; <jats:italic toggle=\"yes\">n</jats:italic> = 2,283, MonoVD; <jats:italic toggle=\"yes\">n</jats:italic> = 877, PolyVD), participants with PolyVD had the highest rates of severe PD. On binary logistic regression analysis, severe PD was independently associated with MonoVD (odds ratio, 1.32; 95% CI, 1.09 to 1.61; <jats:italic toggle=\"yes\">P</jats:italic> = 0.005) and PolyVD (odds ratio, 1.57; 95% CI, 1.16 to 2.13; <jats:italic toggle=\"yes\">P</jats:italic> = 0.004). During a median follow-up of 5.5 y (95% CI, 5.3 to 5.6), a trend toward higher major adverse cardiovascular event rates was observed in individuals with ASCVD and the highest clinical attachment loss tertile. However, no independent association of mean clinical attachment loss with adverse events was noted. PD is highly prevalent in patients with more extensive ASCVD, and severe PD is associated with MonoVD and PolyVD. However, no association of PD with major adverse cardiovascular events was noted. These data suggest that PD may be associated with cardiovascular risk in the population.","PeriodicalId":15596,"journal":{"name":"Journal of Dental Research","volume":"100 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145311096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chronic apical periodontitis (CAP), an inflammatory disease of periapical tissues, leads to alveolar bone destruction. Current therapies lack osteoblast-targeting specificity and fail to effectively promote bone repair. Extracellular vesicles (EVs), particularly milk-derived EVs (MEVs), show potential for bone regeneration and have anti-inflammatory effects. We investigated the therapeutic potential of engineered MEVs modified with the osteoblast-targeting peptide DSPE-PEG-Mal-Cys-SDSSD (DPS) in CAP. DPS-MEVs enhanced osteogenic capacity and exhibited greater osteoblast targeting compared with unmodified MEVs through oxidative phosphorylation (OXPHOS) activation, driven by Kruppel-like factor 4 (KLF4)-mediated upregulation of NADH dehydrogenase 1 alpha subcomplex 4 (Ndufa4) in vivo and in vitro. We also transplanted DPS-MEVs into a CAP model of dogs through apical microsurgery and found that DPS-MEVs enhanced bone repair and reduced inflammation by promoting polarization of M2 macrophages. These findings highlighted the potential of engineered DPS-MEVs as a dual-functional therapy for CAP, combining immunomodulation and tissue repair to advance precision treatment for inflammatory bone diseases.
{"title":"Milk EVs Promote Apical Periodontitis Bone Repair via Osteoblast Targeting.","authors":"S-X Wu,Q-Y Song,H Bai,Y-R Shang,Z-R Yan,M Xia,L-N Wang,M Dong,W-D Niu","doi":"10.1177/00220345251368767","DOIUrl":"https://doi.org/10.1177/00220345251368767","url":null,"abstract":"Chronic apical periodontitis (CAP), an inflammatory disease of periapical tissues, leads to alveolar bone destruction. Current therapies lack osteoblast-targeting specificity and fail to effectively promote bone repair. Extracellular vesicles (EVs), particularly milk-derived EVs (MEVs), show potential for bone regeneration and have anti-inflammatory effects. We investigated the therapeutic potential of engineered MEVs modified with the osteoblast-targeting peptide DSPE-PEG-Mal-Cys-SDSSD (DPS) in CAP. DPS-MEVs enhanced osteogenic capacity and exhibited greater osteoblast targeting compared with unmodified MEVs through oxidative phosphorylation (OXPHOS) activation, driven by Kruppel-like factor 4 (KLF4)-mediated upregulation of NADH dehydrogenase 1 alpha subcomplex 4 (Ndufa4) in vivo and in vitro. We also transplanted DPS-MEVs into a CAP model of dogs through apical microsurgery and found that DPS-MEVs enhanced bone repair and reduced inflammation by promoting polarization of M2 macrophages. These findings highlighted the potential of engineered DPS-MEVs as a dual-functional therapy for CAP, combining immunomodulation and tissue repair to advance precision treatment for inflammatory bone diseases.","PeriodicalId":15596,"journal":{"name":"Journal of Dental Research","volume":"36 1","pages":"220345251368767"},"PeriodicalIF":7.6,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145311449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-18DOI: 10.1177/00220345251381690
N Dritsch,C Bedos,J-N Vergnes
Despite substantial clinical progress under the biomedical paradigm, global oral disease burdens remain high, highlighting the need for integrated and context-sensitive models. This critical review examines how systems sciences can contribute to redefining dentistry's role within contemporary health systems. While systems thinking dates back nearly a century, its application to dental research and policy has expanded significantly in recent years. The objectives of this review are to assess the relevance of systems sciences in addressing current health challenges involving dentistry and to analyze how these approaches have informed dental science and practice to date. Based on a thematic analysis of the literature, the review identifies emerging conceptual frameworks, practical applications across multiple dental domains, and areas requiring further exploration. The review distinguishes between predictive approaches, such as simulation and modeling, and relational paradigms rooted in interdependence, context, and goal-oriented dynamics. It documents recent applications of these frameworks in public health, clinical planning, education, environmental strategy, and patient care. Three widely shared assumptions are finally revisited through systems sciences perspectives: the framing of "oral health" as an isolated individual outcome, the dichotomy between "prevention" and "treatment," and the notion that oral diseases are largely "preventable." While such assumptions may serve communication or policy purposes, they can obscure structural determinants and limit systemic integration of actions against the burden of oral diseases. Systems sciences provide methodological and conceptual tools to reposition dentistry as a contributor to broader health goals: reducing population-level treatment needs, improving access, and addressing upstream determinants of health. Rather than promoting technical growth alone, dental research should place greater emphasis on systemic approaches to ensure that available resources effectively serve population needs. As a scientific framework, systems sciences are not only compatible with these aims but are also essential to achieving them in a coherent, evidence-based, and socially relevant manner.
{"title":"Systems Sciences in Dentistry: A Critical Review.","authors":"N Dritsch,C Bedos,J-N Vergnes","doi":"10.1177/00220345251381690","DOIUrl":"https://doi.org/10.1177/00220345251381690","url":null,"abstract":"Despite substantial clinical progress under the biomedical paradigm, global oral disease burdens remain high, highlighting the need for integrated and context-sensitive models. This critical review examines how systems sciences can contribute to redefining dentistry's role within contemporary health systems. While systems thinking dates back nearly a century, its application to dental research and policy has expanded significantly in recent years. The objectives of this review are to assess the relevance of systems sciences in addressing current health challenges involving dentistry and to analyze how these approaches have informed dental science and practice to date. Based on a thematic analysis of the literature, the review identifies emerging conceptual frameworks, practical applications across multiple dental domains, and areas requiring further exploration. The review distinguishes between predictive approaches, such as simulation and modeling, and relational paradigms rooted in interdependence, context, and goal-oriented dynamics. It documents recent applications of these frameworks in public health, clinical planning, education, environmental strategy, and patient care. Three widely shared assumptions are finally revisited through systems sciences perspectives: the framing of \"oral health\" as an isolated individual outcome, the dichotomy between \"prevention\" and \"treatment,\" and the notion that oral diseases are largely \"preventable.\" While such assumptions may serve communication or policy purposes, they can obscure structural determinants and limit systemic integration of actions against the burden of oral diseases. Systems sciences provide methodological and conceptual tools to reposition dentistry as a contributor to broader health goals: reducing population-level treatment needs, improving access, and addressing upstream determinants of health. Rather than promoting technical growth alone, dental research should place greater emphasis on systemic approaches to ensure that available resources effectively serve population needs. As a scientific framework, systems sciences are not only compatible with these aims but are also essential to achieving them in a coherent, evidence-based, and socially relevant manner.","PeriodicalId":15596,"journal":{"name":"Journal of Dental Research","volume":"13 1","pages":"220345251381690"},"PeriodicalIF":7.6,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145311450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-18DOI: 10.1177/00220345251355267
Y Jin,J Du,Z Wang,S Ge,B Ma
Periodontitis is a chronic inflammatory disease triggered by pathogenic bacteria, with intracellular bacteria and biofilm contributing to persistent periodontal inflammation. In this context, macrophages can be portrayed as a privileged niche for long-term bacterial colonization, leading to further disruption of the immune microenvironment rather than its modulation. Here, a macrophage-targeted metal-organic/polyphenol self-assembly nano drug delivery system was designed for on-site drug delivery and microenvironment restoration. The nanoparticles were synthesized by hyaluronic acid functionalization on the surface of curcumin (Cur)-loaded zeolitic imidazolate framework-8 (denoted as ZCH NPs). ZCH NPs selectively targeted macrophages through CD44 receptor-mediated endocytosis. Following cellular uptake, the nanoparticles underwent pH-responsive degradation in the acidic lysosomal environment (~pH5), releasing zinc ions and Cur. The dual release exerted optimal therapeutic effects, including anti-inflammatory and immunomodulatory activities, through the PPAR/Notch signaling pathways. Furthermore, ZCH NPs restored the osteogenic potential of stem cells in an inflammatory environment by rebalancing the immune microenvironment. ZCH NPs also eliminated extracellular and intracellular bacteria and inhibited biofilm formation. Ultimately, ZCH NPs alleviated inflammatory bone resorption in rat experimental periodontitis, with the reduction of cementoenamel junction-alveolar bone crest from ~568 to ~250 µm. Therefore, periodontal tissue regeneration was promoted by eradicating pathogenic bacteria, modulating immune response, and facilitating osteogenic differentiation. Collectively, through on-site and responsive drug delivery, ZCH NPs exhibited superior efficacy in treating periodontitis, providing a promising strategy for addressing infection-related chronic inflammatory diseases.
{"title":"Macrophage-Targeted Self-Assembled Nanosystem for Periodontitis Treatment.","authors":"Y Jin,J Du,Z Wang,S Ge,B Ma","doi":"10.1177/00220345251355267","DOIUrl":"https://doi.org/10.1177/00220345251355267","url":null,"abstract":"Periodontitis is a chronic inflammatory disease triggered by pathogenic bacteria, with intracellular bacteria and biofilm contributing to persistent periodontal inflammation. In this context, macrophages can be portrayed as a privileged niche for long-term bacterial colonization, leading to further disruption of the immune microenvironment rather than its modulation. Here, a macrophage-targeted metal-organic/polyphenol self-assembly nano drug delivery system was designed for on-site drug delivery and microenvironment restoration. The nanoparticles were synthesized by hyaluronic acid functionalization on the surface of curcumin (Cur)-loaded zeolitic imidazolate framework-8 (denoted as ZCH NPs). ZCH NPs selectively targeted macrophages through CD44 receptor-mediated endocytosis. Following cellular uptake, the nanoparticles underwent pH-responsive degradation in the acidic lysosomal environment (~pH5), releasing zinc ions and Cur. The dual release exerted optimal therapeutic effects, including anti-inflammatory and immunomodulatory activities, through the PPAR/Notch signaling pathways. Furthermore, ZCH NPs restored the osteogenic potential of stem cells in an inflammatory environment by rebalancing the immune microenvironment. ZCH NPs also eliminated extracellular and intracellular bacteria and inhibited biofilm formation. Ultimately, ZCH NPs alleviated inflammatory bone resorption in rat experimental periodontitis, with the reduction of cementoenamel junction-alveolar bone crest from ~568 to ~250 µm. Therefore, periodontal tissue regeneration was promoted by eradicating pathogenic bacteria, modulating immune response, and facilitating osteogenic differentiation. Collectively, through on-site and responsive drug delivery, ZCH NPs exhibited superior efficacy in treating periodontitis, providing a promising strategy for addressing infection-related chronic inflammatory diseases.","PeriodicalId":15596,"journal":{"name":"Journal of Dental Research","volume":"11 1","pages":"220345251355267"},"PeriodicalIF":7.6,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145311481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-18DOI: 10.1177/00220345251370240
F Nie,S Wang,H Tian,J Zhang,Q Yin,J Ju,P Gong,J Liu,P Yang,C Yang
Inflammation is an enabling characteristic that contributes to the acquisition of hallmarks of cancer. Epidemiological studies have suggested a potential connection between periodontitis and increased risk of cancer. However, the underlying mechanisms of this connection remain insufficiently studied. Here, we found that periodontitis promoted the progression of oral squamous cell carcinoma and prostate cancer and fostered an immunosuppressive tumor microenvironment (iTME) characterized by expanded myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages, and regulatory T cells in mouse models. Periodontitis also enhanced the immunosuppressive function of MDSCs and decreased the infiltration of CD8+ T cells. Moreover, periodontitis-induced systemic inflammation remodeled the bone marrow (BM) ecosystem, resulting in myeloid-biased hematopoiesis, which was accompanied by expansion of hematopoietic progenitors (LSK), multipotent progenitor 3 (MPP3), and granulocyte-monocyte precursors, followed by the subsequent augmentation of myeloid cell production. Mechanistically, interleukin (IL)-1 signaling, triggered by periodontitis, induced alterations in the myelopoiesis program. The conditional inhibition of IL-1R1 in the BM attenuated the tumor-promoting effect of periodontitis, diminished abnormal myeloid overproduction, and improved the TME. Thus, these findings reveal that periodontitis remotely induces a myeloid bias in hematopoietic stem and progenitor cells, and that the IL-1-mediated periodontitis-BM axis serves as a critical mechanism for periodontitis-facilitated tumor development and iTME establishment.
{"title":"Periodontitis Promotes OSCC and Prostate Cancer Progression and Immunosuppression by Skewing Myeloid Differentiation of HSPCs.","authors":"F Nie,S Wang,H Tian,J Zhang,Q Yin,J Ju,P Gong,J Liu,P Yang,C Yang","doi":"10.1177/00220345251370240","DOIUrl":"https://doi.org/10.1177/00220345251370240","url":null,"abstract":"Inflammation is an enabling characteristic that contributes to the acquisition of hallmarks of cancer. Epidemiological studies have suggested a potential connection between periodontitis and increased risk of cancer. However, the underlying mechanisms of this connection remain insufficiently studied. Here, we found that periodontitis promoted the progression of oral squamous cell carcinoma and prostate cancer and fostered an immunosuppressive tumor microenvironment (iTME) characterized by expanded myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages, and regulatory T cells in mouse models. Periodontitis also enhanced the immunosuppressive function of MDSCs and decreased the infiltration of CD8+ T cells. Moreover, periodontitis-induced systemic inflammation remodeled the bone marrow (BM) ecosystem, resulting in myeloid-biased hematopoiesis, which was accompanied by expansion of hematopoietic progenitors (LSK), multipotent progenitor 3 (MPP3), and granulocyte-monocyte precursors, followed by the subsequent augmentation of myeloid cell production. Mechanistically, interleukin (IL)-1 signaling, triggered by periodontitis, induced alterations in the myelopoiesis program. The conditional inhibition of IL-1R1 in the BM attenuated the tumor-promoting effect of periodontitis, diminished abnormal myeloid overproduction, and improved the TME. Thus, these findings reveal that periodontitis remotely induces a myeloid bias in hematopoietic stem and progenitor cells, and that the IL-1-mediated periodontitis-BM axis serves as a critical mechanism for periodontitis-facilitated tumor development and iTME establishment.","PeriodicalId":15596,"journal":{"name":"Journal of Dental Research","volume":"19 1","pages":"220345251370240"},"PeriodicalIF":7.6,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145311443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-18DOI: 10.1177/00220345251366952
Y Sohn,H J Jeong,J Park
Diabetes-associated periodontitis has long been attributed to hyperglycemia, primarily through advanced glycation end products (AGEs) and RAGE-mediated oxidative stress. However, recent clinical and experimental findings show that periodontitis risk persists even under good glycemic control, suggesting additional pathological factors. This review highlights hyperinsulinemia-a hallmark of insulin resistance and early-stage type 2 diabetes-as a distinct and underappreciated contributor. In mouse models, excessive insulin signaling in insulin-responsive immune cells, such as T cells and macrophages, promotes proinflammatory polarization, while insulin receptor knockout suppresses immune activation, underscoring insulin's direct immunomodulatory role. Hyperinsulinemia also drives adipose tissue dysfunction and lipotoxicity, amplifying systemic inflammation and elevating circulating cytokines such as interleukin-6 and tumor necrosis factor-α, which may affect periodontal tissues. Moreover, in vivo studies show that insulin excess induces endothelial activation and leukocyte recruitment via CX3CL1 and angiopoietin-2 signaling. Human clamp studies further demonstrate increased levels of inflammatory mediators under euglycemic hyperinsulinemia. Collectively, these findings support a model wherein hyperinsulinemia may contribute to periodontal inflammation and bone loss through mechanisms that are independent of blood glucose levels.
{"title":"The Link between Hyperinsulinemia and Periodontitis in Diabetics.","authors":"Y Sohn,H J Jeong,J Park","doi":"10.1177/00220345251366952","DOIUrl":"https://doi.org/10.1177/00220345251366952","url":null,"abstract":"Diabetes-associated periodontitis has long been attributed to hyperglycemia, primarily through advanced glycation end products (AGEs) and RAGE-mediated oxidative stress. However, recent clinical and experimental findings show that periodontitis risk persists even under good glycemic control, suggesting additional pathological factors. This review highlights hyperinsulinemia-a hallmark of insulin resistance and early-stage type 2 diabetes-as a distinct and underappreciated contributor. In mouse models, excessive insulin signaling in insulin-responsive immune cells, such as T cells and macrophages, promotes proinflammatory polarization, while insulin receptor knockout suppresses immune activation, underscoring insulin's direct immunomodulatory role. Hyperinsulinemia also drives adipose tissue dysfunction and lipotoxicity, amplifying systemic inflammation and elevating circulating cytokines such as interleukin-6 and tumor necrosis factor-α, which may affect periodontal tissues. Moreover, in vivo studies show that insulin excess induces endothelial activation and leukocyte recruitment via CX3CL1 and angiopoietin-2 signaling. Human clamp studies further demonstrate increased levels of inflammatory mediators under euglycemic hyperinsulinemia. Collectively, these findings support a model wherein hyperinsulinemia may contribute to periodontal inflammation and bone loss through mechanisms that are independent of blood glucose levels.","PeriodicalId":15596,"journal":{"name":"Journal of Dental Research","volume":"109 1","pages":"220345251366952"},"PeriodicalIF":7.6,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145311445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-18DOI: 10.1177/00220345251371674
Y Zhang,L Xu,H Yang,J Yu,X Xu,Q Liu,J Xu,Y Wu,W Zou,M Wang
The temporomandibular joint (TMJ) has a close biomechanical relationship with dental occlusion. PIEZO1 is a major mechanosensor in chondrocytes. The role Piezo1 plays in TMJ chondrocytes under aberrant occlusion loading remains obscure. In vivo, cell lineage tracing methods and tissue-specific genetic mutation techniques were adopted. An in vitro chondrocyte stretch loading model and the in vivo unilateral anterior crossbite (UAC) model were used. PIEZO1 was highly expressed in SOX9-, type II collagen (Col-II)-, and type-X collagen (Col-X)-expressing TMJ chondrocytes, and the expression was promoted by UAC stimulation. PIEZO1 was also expressed in ADTC5 cells, and the expression was promoted by stretch loading. Piezo1 knockout by gRNA, a kind of CRISPR-Cas9, led ADTC5 cells to pyroptosis, the process of which was enhanced by stretch loading. Mutation of Piezo1 in Sox9-, Col2-, or Col10-tissue-specific patterns led to pyroptosis of the SOX9-, Col-II-, or Col-X-expressing cells, respectively. The pyroptosis signs were more severe after UAC treatment. The pyroptosis signs were also significant in SOX9- or Col-II-positive cells in the Col10CreER; Piezo1-/- mice at 3 wk but not at 1 wk. After being treated by UAC, the pyroptosis signs at 1 wk turned to be significant in SOX9- and Col-II-positive cells in the Col10CreER; Piezo1-/- mice. Stretch loading plus gRNA2 promoted interleukin-18 (IL-18) secretion by ATDC5 cells. By adding anti-IL-18 blocked protein into the culture medium obtained from the ATDC5 cells treated with stretch loading and gRNA2, the impact of the secreted IL-18 on chondrocyte pyroptosis was confirmed. Conclusions. Piezo1 mutation leads to pyroptosis of not only the mutated cells but also the neighboring cells, especially under aberrant loading, owing to the inflammatory effect of the mutated chondrocytes. Piezo1 takes the role of the inflammation barrier in chondrocytes under aberrant loading. Our findings provide a better understanding of the relationship between mechanical stimulation and inflammation in osteoarthritic cartilage.
{"title":"Inflammation Barrier Role of Piezo1 in Chondrocytes under Aberrant Loading.","authors":"Y Zhang,L Xu,H Yang,J Yu,X Xu,Q Liu,J Xu,Y Wu,W Zou,M Wang","doi":"10.1177/00220345251371674","DOIUrl":"https://doi.org/10.1177/00220345251371674","url":null,"abstract":"The temporomandibular joint (TMJ) has a close biomechanical relationship with dental occlusion. PIEZO1 is a major mechanosensor in chondrocytes. The role Piezo1 plays in TMJ chondrocytes under aberrant occlusion loading remains obscure. In vivo, cell lineage tracing methods and tissue-specific genetic mutation techniques were adopted. An in vitro chondrocyte stretch loading model and the in vivo unilateral anterior crossbite (UAC) model were used. PIEZO1 was highly expressed in SOX9-, type II collagen (Col-II)-, and type-X collagen (Col-X)-expressing TMJ chondrocytes, and the expression was promoted by UAC stimulation. PIEZO1 was also expressed in ADTC5 cells, and the expression was promoted by stretch loading. Piezo1 knockout by gRNA, a kind of CRISPR-Cas9, led ADTC5 cells to pyroptosis, the process of which was enhanced by stretch loading. Mutation of Piezo1 in Sox9-, Col2-, or Col10-tissue-specific patterns led to pyroptosis of the SOX9-, Col-II-, or Col-X-expressing cells, respectively. The pyroptosis signs were more severe after UAC treatment. The pyroptosis signs were also significant in SOX9- or Col-II-positive cells in the Col10CreER; Piezo1-/- mice at 3 wk but not at 1 wk. After being treated by UAC, the pyroptosis signs at 1 wk turned to be significant in SOX9- and Col-II-positive cells in the Col10CreER; Piezo1-/- mice. Stretch loading plus gRNA2 promoted interleukin-18 (IL-18) secretion by ATDC5 cells. By adding anti-IL-18 blocked protein into the culture medium obtained from the ATDC5 cells treated with stretch loading and gRNA2, the impact of the secreted IL-18 on chondrocyte pyroptosis was confirmed. Conclusions. Piezo1 mutation leads to pyroptosis of not only the mutated cells but also the neighboring cells, especially under aberrant loading, owing to the inflammatory effect of the mutated chondrocytes. Piezo1 takes the role of the inflammation barrier in chondrocytes under aberrant loading. Our findings provide a better understanding of the relationship between mechanical stimulation and inflammation in osteoarthritic cartilage.","PeriodicalId":15596,"journal":{"name":"Journal of Dental Research","volume":"20 1","pages":"220345251371674"},"PeriodicalIF":7.6,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145311479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-18DOI: 10.1177/00220345251364167
S Tubert-Jeannin,L Bénézet,A Mulliez,S Listl
In 2019, France implemented a large-scale reform aimed at reducing out-of-pocket health care expenditures, with the objective of preventing the forgoing of dental care for financial reasons. The aim of this study was to assess the impacts of this reform on dental care utilization, with a focus on full dentures as prosthetic care, which was the main target of the reform. The study was based on analyses of large-volume administrative data from the French social health insurance funds and comprised >1 billion dental treatments encountered in the years 2014 to 2023. Drawing from a quasi-experimental research design and segmented negative binomial regression, controlled interrupted time series analyses were conducted with a "control outcome" approach. Controlled interrupted time series analyses compared utilization rates for various types of care whose coverage was differentially affected by the reform. Models were adjusted for COVID-19 and seasonality covariates and stratified by socioeconomic status. Following the removal of out-of-pocket payments for resin-based full dentures, their utilization was 58.85% higher (95% CI, 37.18% to 83.95%) as compared with the control scenario. The utilization of other types of dental care, largely unaffected by the reform, remained unchanged. Prophylactic care use increased only slightly during the study period. These findings suggest that the removal of out-of-pocket expenditures through the French 100% santé reform led to higher utilization of full dentures. However, as the reform focuses on specific treatment items and mainly concerns patients with voluntary health insurance, the impacts of the reform should be carefully monitored in the future, particularly its effects on vulnerable populations.
{"title":"The French 100% Santé Reform: Impacts on Dental Care Utilization.","authors":"S Tubert-Jeannin,L Bénézet,A Mulliez,S Listl","doi":"10.1177/00220345251364167","DOIUrl":"https://doi.org/10.1177/00220345251364167","url":null,"abstract":"In 2019, France implemented a large-scale reform aimed at reducing out-of-pocket health care expenditures, with the objective of preventing the forgoing of dental care for financial reasons. The aim of this study was to assess the impacts of this reform on dental care utilization, with a focus on full dentures as prosthetic care, which was the main target of the reform. The study was based on analyses of large-volume administrative data from the French social health insurance funds and comprised >1 billion dental treatments encountered in the years 2014 to 2023. Drawing from a quasi-experimental research design and segmented negative binomial regression, controlled interrupted time series analyses were conducted with a \"control outcome\" approach. Controlled interrupted time series analyses compared utilization rates for various types of care whose coverage was differentially affected by the reform. Models were adjusted for COVID-19 and seasonality covariates and stratified by socioeconomic status. Following the removal of out-of-pocket payments for resin-based full dentures, their utilization was 58.85% higher (95% CI, 37.18% to 83.95%) as compared with the control scenario. The utilization of other types of dental care, largely unaffected by the reform, remained unchanged. Prophylactic care use increased only slightly during the study period. These findings suggest that the removal of out-of-pocket expenditures through the French 100% santé reform led to higher utilization of full dentures. However, as the reform focuses on specific treatment items and mainly concerns patients with voluntary health insurance, the impacts of the reform should be carefully monitored in the future, particularly its effects on vulnerable populations.","PeriodicalId":15596,"journal":{"name":"Journal of Dental Research","volume":"55 1","pages":"220345251364167"},"PeriodicalIF":7.6,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145311447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-18DOI: 10.1177/00220345251369411
Y. Tang, M. Bie, Q. Zhang, R. Cong, C. Pan, Y. Xia, F. Kang
While the biological functions and molecular mechanisms of osteoclasts in condylar morphogenesis remain incompletely characterized, and the regulatory effects of hypoxic conditions within the deep condyle on osteoclast-mediated alveolar bone remodeling are poorly understood, this investigation systematically examines the hypoxia response mechanisms of cathepsin K–positive (ctsk + ) osteoclasts and their specialized functions in condylar tissue organization. Genetic ablation of ctsk+ cells in diphtheria toxin receptor (DTR) transgenic mice resulted in pronounced accumulation of calcified cartilage within the mandibular condylar cartilage (MCC) accompanied by impaired subchondral bone formation—phenotypes directly attributable to osteoclast deficiency. Intriguingly, DTR animals exhibited concurrent upregulation of chondroblast markers, osteoblastic factors, and bone resorption mediators, suggesting that ctsk+ cells normally function to restrain MCC proliferation and premature hypertrophy while simultaneously inhibiting subchondral osteogenesis. Conditional knockout of hypoxia-inducible factor-1α (HIF-1α) specifically in ctsk+ cells (HIF-1α ∆ctsk-cre ) replicated the cartilage accumulation phenotype observed in DTR mice during early development (≤5 wk), with comparable disorganization of the fibrocartilage layers. However, after 6 wk, HIF-1α ∆ctsk-cre mutants displayed paradoxical cartilage reduction coupled with accelerated subchondral mineralization. We propose that progressive osteoclast depletion, combined with extensive chondrocyte apoptosis and elevated matrix metalloproteinase 13 expression, drives the gradual MCC thinning in knockout animals. The sustained osteoclast deficiency appears to disrupt the physiological cartilage-to-bone transition, ultimately causing delayed but exaggerated subchondral mineralization. At the cellular level, HIF-1α deficiency in ctsk+ osteoclasts induced profound structural abnormalities, including disorganized ruffled borders and defective lysosomal biogenesis. Mechanistically, we identified the osteoclast-specific TSC2-mTORC1-TFEB axis as a critical regulator of hypoxia-responsive lysosomal formation. Collectively, these findings establish a novel dual regulatory role for ctsk+ cells: suppressing chondrocyte proliferation, premature hypertrophy, and osteogenesis through bone resorption signaling and mediating HIF-1α–dependent control of osteoclastogenesis and lysosomal function during calcified cartilage degradation.
{"title":"Ctsk + Osteoclasts Orchestrate Condylar Morphogenesis via Hypoxic Lysosome","authors":"Y. Tang, M. Bie, Q. Zhang, R. Cong, C. Pan, Y. Xia, F. Kang","doi":"10.1177/00220345251369411","DOIUrl":"https://doi.org/10.1177/00220345251369411","url":null,"abstract":"While the biological functions and molecular mechanisms of osteoclasts in condylar morphogenesis remain incompletely characterized, and the regulatory effects of hypoxic conditions within the deep condyle on osteoclast-mediated alveolar bone remodeling are poorly understood, this investigation systematically examines the hypoxia response mechanisms of cathepsin K–positive (ctsk <jats:sup>+</jats:sup> ) osteoclasts and their specialized functions in condylar tissue organization. Genetic ablation of ctsk+ cells in diphtheria toxin receptor (DTR) transgenic mice resulted in pronounced accumulation of calcified cartilage within the mandibular condylar cartilage (MCC) accompanied by impaired subchondral bone formation—phenotypes directly attributable to osteoclast deficiency. Intriguingly, DTR animals exhibited concurrent upregulation of chondroblast markers, osteoblastic factors, and bone resorption mediators, suggesting that ctsk+ cells normally function to restrain MCC proliferation and premature hypertrophy while simultaneously inhibiting subchondral osteogenesis. Conditional knockout of hypoxia-inducible factor-1α (HIF-1α) specifically in ctsk+ cells (HIF-1α <jats:sup>∆ctsk-cre</jats:sup> ) replicated the cartilage accumulation phenotype observed in DTR mice during early development (≤5 wk), with comparable disorganization of the fibrocartilage layers. However, after 6 wk, HIF-1α <jats:sup>∆ctsk-cre</jats:sup> mutants displayed paradoxical cartilage reduction coupled with accelerated subchondral mineralization. We propose that progressive osteoclast depletion, combined with extensive chondrocyte apoptosis and elevated matrix metalloproteinase 13 expression, drives the gradual MCC thinning in knockout animals. The sustained osteoclast deficiency appears to disrupt the physiological cartilage-to-bone transition, ultimately causing delayed but exaggerated subchondral mineralization. At the cellular level, HIF-1α deficiency in ctsk+ osteoclasts induced profound structural abnormalities, including disorganized ruffled borders and defective lysosomal biogenesis. Mechanistically, we identified the osteoclast-specific TSC2-mTORC1-TFEB axis as a critical regulator of hypoxia-responsive lysosomal formation. Collectively, these findings establish a novel dual regulatory role for ctsk+ cells: suppressing chondrocyte proliferation, premature hypertrophy, and osteogenesis through bone resorption signaling and mediating HIF-1α–dependent control of osteoclastogenesis and lysosomal function during calcified cartilage degradation.","PeriodicalId":15596,"journal":{"name":"Journal of Dental Research","volume":"91 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145311097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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