Pub Date : 2025-10-18DOI: 10.1177/00220345251372890
P R Arany,M Charles-Ayinde,M Fontana,G Huang,S M Levy,D V Messadi,R Moffat,S Naavaal,S L Tomar,Y H Yu,C H Fox
Topical fluorides play a critical role in the prevention and management of dental caries and have been a cornerstone of evidence-based oral health promotion for decades. A rigorous understanding of the improved acid resistance of fluorapatite, with more recent evidence of the antimicrobial actions of fluorides, has helped establish its key role in caries management. The American Association for Dental, Oral, and Craniofacial Research (AADOCR) recommends using fluoride-containing dentifrices at 1,000 to 1,500 ppm twice daily based on the current evidence. For preschool-aged children, only a small amount (a smear about the size of a grain of rice) should be used to effectively prevent caries while minimizing the risk of dental fluorosis from unintentional ingestion. Furthermore, for patients at increased caries risk, the use of topical fluoride agents, such as professionally applied gels, varnishes, and/or silver diamine fluoride, could be used at 6-mo intervals, along with daily or weekly fluoride mouth rinses and gels; frequency should be adjusted to individual risk status and other sources of fluorides. Due to their high fluoride concentration, mouth rinses and prescription gels are not recommended for preschool-aged children. The AADOCR supports continued high-quality research to refine clinical guidelines and ensure that topical fluoride use remains aligned with scientific understanding and public health priorities.
{"title":"The AADOCR Position Statement on Topical Fluoride.","authors":"P R Arany,M Charles-Ayinde,M Fontana,G Huang,S M Levy,D V Messadi,R Moffat,S Naavaal,S L Tomar,Y H Yu,C H Fox","doi":"10.1177/00220345251372890","DOIUrl":"https://doi.org/10.1177/00220345251372890","url":null,"abstract":"Topical fluorides play a critical role in the prevention and management of dental caries and have been a cornerstone of evidence-based oral health promotion for decades. A rigorous understanding of the improved acid resistance of fluorapatite, with more recent evidence of the antimicrobial actions of fluorides, has helped establish its key role in caries management. The American Association for Dental, Oral, and Craniofacial Research (AADOCR) recommends using fluoride-containing dentifrices at 1,000 to 1,500 ppm twice daily based on the current evidence. For preschool-aged children, only a small amount (a smear about the size of a grain of rice) should be used to effectively prevent caries while minimizing the risk of dental fluorosis from unintentional ingestion. Furthermore, for patients at increased caries risk, the use of topical fluoride agents, such as professionally applied gels, varnishes, and/or silver diamine fluoride, could be used at 6-mo intervals, along with daily or weekly fluoride mouth rinses and gels; frequency should be adjusted to individual risk status and other sources of fluorides. Due to their high fluoride concentration, mouth rinses and prescription gels are not recommended for preschool-aged children. The AADOCR supports continued high-quality research to refine clinical guidelines and ensure that topical fluoride use remains aligned with scientific understanding and public health priorities.","PeriodicalId":15596,"journal":{"name":"Journal of Dental Research","volume":"1 1","pages":"220345251372890"},"PeriodicalIF":7.6,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145311478","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}
Resin–dentin bonding technology is the primary method for tooth restoration in clinical practice. However, the formation of a defect zone at the bonding interface due to inadequate moisture control at the interface remains a major challenge. Inspired by mussel wet-adhesion mechanisms, this study functionalized phosphoric acid etchants with catechol–lysine–methacrylate (CLM), a polymerizable small-molecule monomer. During dentin demineralization, catechol binding to demineralized dentin was confirmed using an incubation-rinsing technique, while lysine’s role in facilitating rapid water release at the bonding interface was validated by freeze-drying mass loss, surface charge distribution, and thermogravimetric analysis. Confocal laser scanning microscopy revealed increased resin tag lengths in the CLM-treated groups, indicating enhanced resin infiltration. Ultimate tensile strength, dry mass loss, sodium dodecyl sulfate–polyacrylamide gel electrophoresis, and in situ zymography demonstrated catechol-enabled collagen stabilization via Schiff base/ester bonds and endogenous enzyme inhibition. Micro-tensile testing revealed that the 4- to 5-mg/mL CLM groups maintained bond strength after 10,000 thermal cycles. Thus, CLM-functionalized etchants may enhance bonding durability in vitro by improving moisture control and collagen stability.
{"title":"Mussel-Inspired Etchant with Catechol-Lys-Methacrylate for Bond Durability","authors":"Y.T. Hu, C.Y. Yang, D.J. Wang, X.R. Feng, F.R. Tay, J.H. Chen, X.D. Xing, Y.H. Xiao, L. Zhang","doi":"10.1177/00220345251376314","DOIUrl":"https://doi.org/10.1177/00220345251376314","url":null,"abstract":"Resin–dentin bonding technology is the primary method for tooth restoration in clinical practice. However, the formation of a defect zone at the bonding interface due to inadequate moisture control at the interface remains a major challenge. Inspired by mussel wet-adhesion mechanisms, this study functionalized phosphoric acid etchants with catechol–lysine–methacrylate (CLM), a polymerizable small-molecule monomer. During dentin demineralization, catechol binding to demineralized dentin was confirmed using an incubation-rinsing technique, while lysine’s role in facilitating rapid water release at the bonding interface was validated by freeze-drying mass loss, surface charge distribution, and thermogravimetric analysis. Confocal laser scanning microscopy revealed increased resin tag lengths in the CLM-treated groups, indicating enhanced resin infiltration. Ultimate tensile strength, dry mass loss, sodium dodecyl sulfate–polyacrylamide gel electrophoresis, and in situ zymography demonstrated catechol-enabled collagen stabilization via Schiff base/ester bonds and endogenous enzyme inhibition. Micro-tensile testing revealed that the 4- to 5-mg/mL CLM groups maintained bond strength after 10,000 thermal cycles. Thus, CLM-functionalized etchants may enhance bonding durability in vitro by improving moisture control and collagen stability.","PeriodicalId":15596,"journal":{"name":"Journal of Dental Research","volume":"142 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145311081","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}
Temporomandibular joint osteoarthritis (TMJOA) is a progressive and debilitating degenerative joint disorder characterized by cartilage degradation. Its pathogenesis remains poorly understood, and current treatment strategies are insufficient to restore normal joint structure. Lipid metabolism disorders in condylar chondrocytes have been identified as key contributors to TMJOA development, with peroxisomes playing an essential regulatory role in this metabolic process. Although previous studies have suggested a role for peroxisomes in chondrocyte biology, their specific involvement in TMJOA pathogenesis remains unclear. This study is the first to demonstrate the involvement of peroxisomes in TMJOA and to elucidate the associated molecular mechanisms. A TMJOA mouse model was established via unilateral anterior crossbite surgery, revealing abnormal peroxisome quantity and function. In vitro experiments demonstrated that inhibiting peroxisome function alleviated mechanical stress-induced OA-like damage to chondrocytes. In Acan-CreERT2 Pex2f/f conditional knockout (KO) mice, Pex2 KO inhibited peroxisome function and significantly attenuated TMJOA pathology. Mechanistically, peroxisome functional inhibition led to decreased levels of palmitic acid (PA), whereas exogenous PA exposure induced an OA-like phenotype in chondrocytes. Further investigation revealed that PA activated the WNT/PCP pathway by activating the JNK/c-JUN signaling axis. Multiomics analysis revealed S100a4 as a key downstream effector gene, and further CUT&RUN quantitative polymerase chain reaction and dual-luciferase reporter assays confirmed that c-JUN directly bound to the S100a4 promoter region (-101 to -94 bp) to regulate its transcription. Knockdown of S100a4 expression significantly reduced PA-induced Mmp13 expression in chondrocytes. In vivo experiments confirmed that intra-articular injection of PA upregulated S100a4 levels and promoted TMJOA development. In conclusion, this study is the first to elucidate the critical role of the peroxisome/PA/JNK/c-JUN/S100a4 axis in cartilage degradation in TMJOA, providing a novel and promising therapeutic target for TMJOA.
{"title":"Peroxisome Functional Inhibition Alleviates TMJOA Cartilage Degradation.","authors":"R Ren,L Xiao,H Qi,S Tang,P Yue,Y Zhang,S Lin,L Xu,Y Li,K Zhou,Z Zhao,J Fang","doi":"10.1177/00220345251381299","DOIUrl":"https://doi.org/10.1177/00220345251381299","url":null,"abstract":"Temporomandibular joint osteoarthritis (TMJOA) is a progressive and debilitating degenerative joint disorder characterized by cartilage degradation. Its pathogenesis remains poorly understood, and current treatment strategies are insufficient to restore normal joint structure. Lipid metabolism disorders in condylar chondrocytes have been identified as key contributors to TMJOA development, with peroxisomes playing an essential regulatory role in this metabolic process. Although previous studies have suggested a role for peroxisomes in chondrocyte biology, their specific involvement in TMJOA pathogenesis remains unclear. This study is the first to demonstrate the involvement of peroxisomes in TMJOA and to elucidate the associated molecular mechanisms. A TMJOA mouse model was established via unilateral anterior crossbite surgery, revealing abnormal peroxisome quantity and function. In vitro experiments demonstrated that inhibiting peroxisome function alleviated mechanical stress-induced OA-like damage to chondrocytes. In Acan-CreERT2 Pex2f/f conditional knockout (KO) mice, Pex2 KO inhibited peroxisome function and significantly attenuated TMJOA pathology. Mechanistically, peroxisome functional inhibition led to decreased levels of palmitic acid (PA), whereas exogenous PA exposure induced an OA-like phenotype in chondrocytes. Further investigation revealed that PA activated the WNT/PCP pathway by activating the JNK/c-JUN signaling axis. Multiomics analysis revealed S100a4 as a key downstream effector gene, and further CUT&RUN quantitative polymerase chain reaction and dual-luciferase reporter assays confirmed that c-JUN directly bound to the S100a4 promoter region (-101 to -94 bp) to regulate its transcription. Knockdown of S100a4 expression significantly reduced PA-induced Mmp13 expression in chondrocytes. In vivo experiments confirmed that intra-articular injection of PA upregulated S100a4 levels and promoted TMJOA development. In conclusion, this study is the first to elucidate the critical role of the peroxisome/PA/JNK/c-JUN/S100a4 axis in cartilage degradation in TMJOA, providing a novel and promising therapeutic target for TMJOA.","PeriodicalId":15596,"journal":{"name":"Journal of Dental Research","volume":"27 1","pages":"220345251381299"},"PeriodicalIF":7.6,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145311444","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: 10.1177/00220345251383829
J K Jeong,H Choi,T H Kim,D Adasooriya,S W Cho,E S Cho
Molar root morphogenesis, particularly the formation of the furcation that determines root number, is a complex process governed by precise epithelial-mesenchymal interactions. Although Wnt signaling is critical for tooth development, the mechanisms that spatially restrict its activity to ensure proper root architecture are not fully understood. In this study, to investigate the role of the secreted Wnt antagonist Notum in regulating molar root furcation, we analyzed Notum knockout (KO) mice. Temporospatial expression analysis revealed that Notum is specifically and transiently expressed in the differentiating odontoblasts of the apical mesenchyme during furcation formation. Notum KO mice exhibited a severe failure of molar root furcation with an enlarged pulp chamber. Mechanistically, particularly at the molar furcation region, Notum deficiency led to impaired extension of Hertwig's epithelial root sheath (HERS) and dysregulated signaling in the underlying mesenchyme, characterized by an upregulated Wnt pathway and, consequently, increased cell proliferation of apical pulp cells and reduced odontoblast differentiation. Notably, inducible deletion of Wntless (Wls) in the dental epithelium phenocopied the furcation defect and led to a dramatic loss of Notum expression, demonstrating that epithelial Wnt signaling is required for Notum induction at the mesenchymal apex of furcation region. These findings identify Notum as a critical regulator of molar root furcation. We propose a model in which HERS-derived Wnt signaling induces Notum expression in the adjacent mesenchyme, which, in turn, antagonizes the Wnt signal to orchestrate the switch from cell proliferation to odontoblastic differentiation, thereby driving the formation of the root furcation. This study provides novel insights into the molecular mechanisms underlying the negative feedback loop between Wnt and Notum through epithelial-mesenchymal interactions, contributing to a deeper understanding of tooth development.
{"title":"Notum Regulates Tooth Root Morphogenesis by Modulating Wnt Signaling.","authors":"J K Jeong,H Choi,T H Kim,D Adasooriya,S W Cho,E S Cho","doi":"10.1177/00220345251383829","DOIUrl":"https://doi.org/10.1177/00220345251383829","url":null,"abstract":"Molar root morphogenesis, particularly the formation of the furcation that determines root number, is a complex process governed by precise epithelial-mesenchymal interactions. Although Wnt signaling is critical for tooth development, the mechanisms that spatially restrict its activity to ensure proper root architecture are not fully understood. In this study, to investigate the role of the secreted Wnt antagonist Notum in regulating molar root furcation, we analyzed Notum knockout (KO) mice. Temporospatial expression analysis revealed that Notum is specifically and transiently expressed in the differentiating odontoblasts of the apical mesenchyme during furcation formation. Notum KO mice exhibited a severe failure of molar root furcation with an enlarged pulp chamber. Mechanistically, particularly at the molar furcation region, Notum deficiency led to impaired extension of Hertwig's epithelial root sheath (HERS) and dysregulated signaling in the underlying mesenchyme, characterized by an upregulated Wnt pathway and, consequently, increased cell proliferation of apical pulp cells and reduced odontoblast differentiation. Notably, inducible deletion of Wntless (Wls) in the dental epithelium phenocopied the furcation defect and led to a dramatic loss of Notum expression, demonstrating that epithelial Wnt signaling is required for Notum induction at the mesenchymal apex of furcation region. These findings identify Notum as a critical regulator of molar root furcation. We propose a model in which HERS-derived Wnt signaling induces Notum expression in the adjacent mesenchyme, which, in turn, antagonizes the Wnt signal to orchestrate the switch from cell proliferation to odontoblastic differentiation, thereby driving the formation of the root furcation. This study provides novel insights into the molecular mechanisms underlying the negative feedback loop between Wnt and Notum through epithelial-mesenchymal interactions, contributing to a deeper understanding of tooth development.","PeriodicalId":15596,"journal":{"name":"Journal of Dental Research","volume":"54 1","pages":"220345251383829"},"PeriodicalIF":7.6,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145311448","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: 10.1177/00220345251378053
J Adeoye,H Wang,A W I Lo,U S Khoo,Y-X Su
Oral cancer often develops from oral potentially malignant disorders. Oral leukoplakia (OL) is the most common oral potentially malignant disorder. However, not all patients with OL develop oral cancer in their lifetimes, and cancer risk assessment is challenging. This study developed a time-to-event artificial intelligence-based model (termed OralCancerPredict) that integrated patient characteristics, histologic features, and immunohistochemical indicators for precise prediction of cancer progression in OL. We performed a retrospective analysis of patient data (n = 456) and tissue samples (n = 1,312) obtained before cancer progression or at last follow-up for patients with OL. KRT13 and p53 immunohistochemistry and quantitative analyses were performed for tissue samples, while independent prognostic features, including demographic characteristics, clinical information, and histopathologic findings, were obtained for patients in the cohort. KRT13 and p53 expression was combined with histologic and patient data for model training, testing, and external validation. Performance evaluation for OralCancerPredict included model discriminative ability, calibration, explainability, and net benefit analysis via decision curves. External validation was also performed to ensure model generalizability based on patient data (n = 119) and tissue samples (n = 322) unused for training and testing. Our findings showed that OralCancerPredict trained on multidimensional data had good concordance indices (0.855 to 0.867), areas under the curve (0.877 to 0.882), and integrated Brier scores (0.046 to 0.069) at testing and external validation. Explainability analysis confirmed the importance of KRT13 and p53 deregulated expression and World Health Organization dysplasia grading to OralCancerPredict in predicting the risk of cancerization and cancer progression-free survival. Moreover, the model had a better net benefit than the World Health Organization and binary dysplasia grading systems alone, which represent the current risk stratification methods in OL management. Overall, OralCancerPredict can predict the risk of cancer development and cancer progression-free survival for patients with OL, with good discrimination, calibration, and net benefit. The explainable artificial intelligence model has the potential to streamline intervention and close monitoring in the clinical management of OL.
{"title":"Multidimensional Artificial Intelligence-Based Cancer Progression Prediction in Oral Leukoplakia.","authors":"J Adeoye,H Wang,A W I Lo,U S Khoo,Y-X Su","doi":"10.1177/00220345251378053","DOIUrl":"https://doi.org/10.1177/00220345251378053","url":null,"abstract":"Oral cancer often develops from oral potentially malignant disorders. Oral leukoplakia (OL) is the most common oral potentially malignant disorder. However, not all patients with OL develop oral cancer in their lifetimes, and cancer risk assessment is challenging. This study developed a time-to-event artificial intelligence-based model (termed OralCancerPredict) that integrated patient characteristics, histologic features, and immunohistochemical indicators for precise prediction of cancer progression in OL. We performed a retrospective analysis of patient data (n = 456) and tissue samples (n = 1,312) obtained before cancer progression or at last follow-up for patients with OL. KRT13 and p53 immunohistochemistry and quantitative analyses were performed for tissue samples, while independent prognostic features, including demographic characteristics, clinical information, and histopathologic findings, were obtained for patients in the cohort. KRT13 and p53 expression was combined with histologic and patient data for model training, testing, and external validation. Performance evaluation for OralCancerPredict included model discriminative ability, calibration, explainability, and net benefit analysis via decision curves. External validation was also performed to ensure model generalizability based on patient data (n = 119) and tissue samples (n = 322) unused for training and testing. Our findings showed that OralCancerPredict trained on multidimensional data had good concordance indices (0.855 to 0.867), areas under the curve (0.877 to 0.882), and integrated Brier scores (0.046 to 0.069) at testing and external validation. Explainability analysis confirmed the importance of KRT13 and p53 deregulated expression and World Health Organization dysplasia grading to OralCancerPredict in predicting the risk of cancerization and cancer progression-free survival. Moreover, the model had a better net benefit than the World Health Organization and binary dysplasia grading systems alone, which represent the current risk stratification methods in OL management. Overall, OralCancerPredict can predict the risk of cancer development and cancer progression-free survival for patients with OL, with good discrimination, calibration, and net benefit. The explainable artificial intelligence model has the potential to streamline intervention and close monitoring in the clinical management of OL.","PeriodicalId":15596,"journal":{"name":"Journal of Dental Research","volume":"1 1","pages":"220345251378053"},"PeriodicalIF":7.6,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145311453","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: 10.1177/00220345251383901
P C Yelick
{"title":"Reimagining Dental, Oral, and Craniofacial Research: New Opportunities for the IADR's Efforts to Achieve Global Oral Health.","authors":"P C Yelick","doi":"10.1177/00220345251383901","DOIUrl":"https://doi.org/10.1177/00220345251383901","url":null,"abstract":"","PeriodicalId":15596,"journal":{"name":"Journal of Dental Research","volume":"194 1","pages":"220345251383901"},"PeriodicalIF":7.6,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145311446","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 : 2025-10-16DOI: 10.1177/00220345251368346
Y Chiba,T Tian,K Yoshizaki,X Wang,A Yamada,S Fukumoto
The coordination of dental cells is essential for tooth development. Various dental epithelial cell types are involved in tooth development, and each cell type plays a distinct role; however, the functional role of the outer enamel epithelium (OEE) remains unclear. We performed single-cell RNA-sequence (scRNA-seq) analysis of postnatal day (P) 7 incisors and embryonic day (E) 14 P1 molars of the mouse tooth germ to reveal the gene expression profile and role of OEE during tooth development. We identified keratin 15 (Krt15) as a specific marker gene of OEE in the dental epithelium. Characterization of dental epithelial clusters using scRNA-seq suggested that Krt15-negative cycling inner enamel epithelial (IEE) cells give rise to Krt15-positive OEE cells, whereas the proliferative activity of dental epithelial cells decreases toward the development of OEE cells. We performed ex vivo organ cultures of the tooth germ to examine the effects of Krt15 knockdown on tooth development. Depletion of Krt15 in the tooth germ resulted in ectopic expression of Ki67 in OEE cells, leading to the development of an abnormal dental epithelial structure. We used the dental epithelial cell line CLDE to assess the molecular mechanisms regulated by Krt15. Krt15-depleted CLDE cells showed abnormal cellular morphology and dysregulated gene expression of cytokeratin family members. Furthermore, Krt15 knockdown in CLDE cells upregulated the expression of cell proliferation marker genes, such as Mki67. Furthermore, Krt15-depleted CLDE cells exhibited activation of the p38 MAP kinase (MAPK) pathway and high proliferative activity. This suggested that Krt15 may control tooth germ size, inhibits p38 activation, and may act as a suppressor of dental epithelial cell proliferation. These findings provide new insights into the role of OEE in tooth development and contribute to a better understanding of the mechanisms underlying tooth morphogenesis.
{"title":"Keratin 15 Regulates Cell Proliferation in Outer Enamel Epithelium.","authors":"Y Chiba,T Tian,K Yoshizaki,X Wang,A Yamada,S Fukumoto","doi":"10.1177/00220345251368346","DOIUrl":"https://doi.org/10.1177/00220345251368346","url":null,"abstract":"The coordination of dental cells is essential for tooth development. Various dental epithelial cell types are involved in tooth development, and each cell type plays a distinct role; however, the functional role of the outer enamel epithelium (OEE) remains unclear. We performed single-cell RNA-sequence (scRNA-seq) analysis of postnatal day (P) 7 incisors and embryonic day (E) 14 P1 molars of the mouse tooth germ to reveal the gene expression profile and role of OEE during tooth development. We identified keratin 15 (Krt15) as a specific marker gene of OEE in the dental epithelium. Characterization of dental epithelial clusters using scRNA-seq suggested that Krt15-negative cycling inner enamel epithelial (IEE) cells give rise to Krt15-positive OEE cells, whereas the proliferative activity of dental epithelial cells decreases toward the development of OEE cells. We performed ex vivo organ cultures of the tooth germ to examine the effects of Krt15 knockdown on tooth development. Depletion of Krt15 in the tooth germ resulted in ectopic expression of Ki67 in OEE cells, leading to the development of an abnormal dental epithelial structure. We used the dental epithelial cell line CLDE to assess the molecular mechanisms regulated by Krt15. Krt15-depleted CLDE cells showed abnormal cellular morphology and dysregulated gene expression of cytokeratin family members. Furthermore, Krt15 knockdown in CLDE cells upregulated the expression of cell proliferation marker genes, such as Mki67. Furthermore, Krt15-depleted CLDE cells exhibited activation of the p38 MAP kinase (MAPK) pathway and high proliferative activity. This suggested that Krt15 may control tooth germ size, inhibits p38 activation, and may act as a suppressor of dental epithelial cell proliferation. These findings provide new insights into the role of OEE in tooth development and contribute to a better understanding of the mechanisms underlying tooth morphogenesis.","PeriodicalId":15596,"journal":{"name":"Journal of Dental Research","volume":"66 1","pages":"220345251368346"},"PeriodicalIF":7.6,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145305734","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 : 2025-10-16DOI: 10.1177/00220345251364162
B Liu,F Cao,S Zheng,X Yuan,N Mandalapu,J S Park,M O Sugihara,Y Mishina,J A Helms
As a first line of defense against periodontal diseases, the junctional epithelium must establish a firm attachment to the tooth surface while allowing new cells arising from the stem cell niche to migrate through the tissue. How these static and dynamic cell behaviors are coordinated in the junctional epithelium is not clear; we hypothesize it involves the epithelial-to-mesenchymal transition (EMT). An intact junctional epithelium was interrogated via quantitative immunohistochemistry for molecular markers of EMT; since EMT is also critical for tissue repair, the junctional epithelium was also interrogated at multiple time points after ligature-induced periodontitis. These analyses revealed that junctional epithelial cells transition from a polarized, cell-adherent phenotype to one in which cytoskeletal remodeling and increased motility occur. To gain insights into molecular mechanisms regulating EMT, we used a genetic system to delete the BMP type I receptor (BMPR1a) in postnatal mice. Within 7 d of BMPR1a inactivation, multiple EMT signaling pathways including Wnt/β-catenin, transforming growth factor-β, and Notch signaling were upregulated in the junctional epithelium. The mutant junctional epithelium exhibited extensive EMT accompanied by downregulation of the hemidesmosomal proteins Laminin5, plectin, and β4 integrin. Together, these findings demonstrate that normal junctional epithelium turnover used EMT and that this physiological process is controlled in part by WNT/BMP signaling.
{"title":"BMP/WNT-Dependent Mechanisms of Junctional Epithelium Turnover.","authors":"B Liu,F Cao,S Zheng,X Yuan,N Mandalapu,J S Park,M O Sugihara,Y Mishina,J A Helms","doi":"10.1177/00220345251364162","DOIUrl":"https://doi.org/10.1177/00220345251364162","url":null,"abstract":"As a first line of defense against periodontal diseases, the junctional epithelium must establish a firm attachment to the tooth surface while allowing new cells arising from the stem cell niche to migrate through the tissue. How these static and dynamic cell behaviors are coordinated in the junctional epithelium is not clear; we hypothesize it involves the epithelial-to-mesenchymal transition (EMT). An intact junctional epithelium was interrogated via quantitative immunohistochemistry for molecular markers of EMT; since EMT is also critical for tissue repair, the junctional epithelium was also interrogated at multiple time points after ligature-induced periodontitis. These analyses revealed that junctional epithelial cells transition from a polarized, cell-adherent phenotype to one in which cytoskeletal remodeling and increased motility occur. To gain insights into molecular mechanisms regulating EMT, we used a genetic system to delete the BMP type I receptor (BMPR1a) in postnatal mice. Within 7 d of BMPR1a inactivation, multiple EMT signaling pathways including Wnt/β-catenin, transforming growth factor-β, and Notch signaling were upregulated in the junctional epithelium. The mutant junctional epithelium exhibited extensive EMT accompanied by downregulation of the hemidesmosomal proteins Laminin5, plectin, and β4 integrin. Together, these findings demonstrate that normal junctional epithelium turnover used EMT and that this physiological process is controlled in part by WNT/BMP signaling.","PeriodicalId":15596,"journal":{"name":"Journal of Dental Research","volume":"37 1","pages":"220345251364162"},"PeriodicalIF":7.6,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145305739","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 : 2025-10-16DOI: 10.1177/00220345251368274
N Lacin,C Sfeir
Magnesium (Mg) has emerged as a promising biomaterial, drawing significant attention for its potential in biomedical applications. As Mg-based products are in several clinical trials and in clinical use, it is timely to summarize the current knowledge of the biological effects and clinical potential with a special emphasis on oral and craniomaxillofacial applications. Mg-based biomaterials offer biocompatibility, biodegradability, and mechanical properties suitable for various clinical applications. These characteristics make them promising alternatives to polymers and permanent metals used in implantable devices, meshes, and fixation plates, effectively addressing challenges such as stress shielding, inflammation, and the need for removal surgeries. Their degradation enables gradual native tissue replacement while providing initial support, which is why most of the devices were developed for bone fixation applications. Clinically, Mg-based biomaterials such as resorbable membranes and bone grafts show potential in guided bone/tissue regeneration. In the United States, there is one FDA-approved Mg-based device for orthopedic applications compared with more regulatory approvals in Europe and Asia (at the time of writing). The main limitations that have delayed their widespread clinical use are the variable site-dependent degradation of Mg and Mg's effect as a biological agent, which adds another layer to the regulatory process. Studies show Mg's pro-osteogenic, anti-osteoclastic, and anti-inflammatory properties. Mg enhances bone regeneration by activating signaling pathways in mesenchymal stem cells and modulating the immune response. As research progresses, innovative Mg delivery systems leveraging its biological properties may utilize the potential of Mg-based biomaterials for advancing regenerative therapies. This review explores the following: (1) the current status of Mg-based biomaterials in clinical applications, (2) the corrosion properties of Mg metal devices and the biological interactions of degradation by-products, (3) the biological and immunomodulatory role of Mg in bone regeneration, and (4) the use of Mg-based biomaterials in oral and maxillofacial bone regeneration.
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Pub Date : 2025-10-16DOI: 10.1177/00220345251366279
Y Ding,J Luan,H S Malmstrom,X Luan,T G H Diekwisch
The interplay between osteogenesis and angiogenesis is an important prerequisite for successful bone regeneration as it provides capillary supply to the initial bone lamellae involved in skeletogenesis. The Wnt signaling pathway is one of the key signaling pathways promoting both osteogenesis and angiogenesis. In the present study, we evaluated the regenerative potential of microRNA-27 (miR-27) by delivering miR-27 mimic via lipid nanoparticles (LNPs) to enhance periodontal tissue repair through the targeted modulation of Secreted Frizzled-Related Protein 1 (SFRP1). Our study demonstrated that inflammatory conditions inhibit the expression and function of miR-27 in a periodontitis model. miR-27 treatment significantly upregulated key modulators of periodontal regeneration, including osteogenic markers (ALP, RUNX2, and COL1) and angiogenic factors (CD31, CD34, and VEGF). This treatment also resulted in increased alkaline phosphatase activity and enhanced mineral deposition, alongside improved spheroid sprouting and tube formation in Matrigel cultures. LNPs were applied to optimize miR-27 delivery for efficient transfection. In vivo implantation revealed that miR-27 accelerated extracellular matrix remodeling in subcutaneous implants, induced a 6-fold increase in neovascularization, and significantly enhanced periodontal tissue formation and bone regeneration, as evidenced by a 43.9% reduction in the distance between the alveolar bone ridge and the cementoenamel junction. Mechanistically, miR-27 promoted osteogenic and angiogenic responses by suppressing SFRP1, a known Wnt signaling inhibitor and validated target of miR-27, thereby activating the Wnt pathway. Together, these studies demonstrate that miR-27 mimic functioned as a bioactive molecule promoting periodontal tissue regeneration through angiogenesis coinciding with osteogenesis. Our study also suggests that the miR-27-LNPs/scaffold combination is an exciting novel agent for the treatment of periodontal disease.
{"title":"Mir-27 Promotes Periodontal Regeneration via Osteogenesis/Angiogenesis.","authors":"Y Ding,J Luan,H S Malmstrom,X Luan,T G H Diekwisch","doi":"10.1177/00220345251366279","DOIUrl":"https://doi.org/10.1177/00220345251366279","url":null,"abstract":"The interplay between osteogenesis and angiogenesis is an important prerequisite for successful bone regeneration as it provides capillary supply to the initial bone lamellae involved in skeletogenesis. The Wnt signaling pathway is one of the key signaling pathways promoting both osteogenesis and angiogenesis. In the present study, we evaluated the regenerative potential of microRNA-27 (miR-27) by delivering miR-27 mimic via lipid nanoparticles (LNPs) to enhance periodontal tissue repair through the targeted modulation of Secreted Frizzled-Related Protein 1 (SFRP1). Our study demonstrated that inflammatory conditions inhibit the expression and function of miR-27 in a periodontitis model. miR-27 treatment significantly upregulated key modulators of periodontal regeneration, including osteogenic markers (ALP, RUNX2, and COL1) and angiogenic factors (CD31, CD34, and VEGF). This treatment also resulted in increased alkaline phosphatase activity and enhanced mineral deposition, alongside improved spheroid sprouting and tube formation in Matrigel cultures. LNPs were applied to optimize miR-27 delivery for efficient transfection. In vivo implantation revealed that miR-27 accelerated extracellular matrix remodeling in subcutaneous implants, induced a 6-fold increase in neovascularization, and significantly enhanced periodontal tissue formation and bone regeneration, as evidenced by a 43.9% reduction in the distance between the alveolar bone ridge and the cementoenamel junction. Mechanistically, miR-27 promoted osteogenic and angiogenic responses by suppressing SFRP1, a known Wnt signaling inhibitor and validated target of miR-27, thereby activating the Wnt pathway. Together, these studies demonstrate that miR-27 mimic functioned as a bioactive molecule promoting periodontal tissue regeneration through angiogenesis coinciding with osteogenesis. Our study also suggests that the miR-27-LNPs/scaffold combination is an exciting novel agent for the treatment of periodontal disease.","PeriodicalId":15596,"journal":{"name":"Journal of Dental Research","volume":"92 1","pages":"220345251366279"},"PeriodicalIF":7.6,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145305738","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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