C Feng, X Dou, S-R Li, X Xu, Z Dang, Z Jiang, E Jiang, Z Shang
{"title":"Single-Cell Insights into Unicystic and Solid Ameloblastoma Heterogeneity.","authors":"C Feng, X Dou, S-R Li, X Xu, Z Dang, Z Jiang, E Jiang, Z Shang","doi":"10.1177/00220345251340892","DOIUrl":"10.1177/00220345251340892","url":null,"abstract":"<p><p>The clinical classification of ameloblastoma (AM) plays a decisive role in the selection of treatment options, but the difference of single-cell landscape among clinical classifications is still unclear. At the same time, there is an urgent need to understand the key cell subtypes that determine the clinical subtypes. We characterized the single-cell transcriptional profiles of clinical subtypes of AM. We also characterized a pseudotime transition trajectory from immunoactive epithelial cells to vascular-associated fibroblasts, identifying key transcription factors involved in this process. Notably, we observed significant heterogeneity between M1 and M2 macrophages among the clinical subtypes of AM. Furthermore, our analysis revealed that metabolic disorder in AM was primarily driven by the metabolic disturbances in M1 and M2 macrophages. At the cellular communication level, we highlighted the role of M2 macrophages in mediating cell interactions, focusing on the RANKL/RANK pathway associated with osteoclast activity. Finally, we attempted to establish a unicystic AM-derived epithelial cell line and utilized it to construct an AM-like organoid model; we found that M2 macrophages competed with AM for L-cysteine to achieve cystic changes in the solid lesion. Our exploration of pathogenesis underlying various clinical types of AM advances our knowledge of AM heterogeneity, offering promising targets for novel therapeutic strategies.</p>","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":" ","pages":"1506-1516"},"PeriodicalIF":5.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144510067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M Zhang, M Yuan, K Asam, Z Gong, T Xie, F Gleber-Netto, M D Santi, Y Kobayashi, E Shimizu, B Aouizerat, M Amit, M D Boada, Y Ye
{"title":"Perineural Invasion Exhibits Traits of Neurodegeneration.","authors":"M Zhang, M Yuan, K Asam, Z Gong, T Xie, F Gleber-Netto, M D Santi, Y Kobayashi, E Shimizu, B Aouizerat, M Amit, M D Boada, Y Ye","doi":"10.1177/00220345251334379","DOIUrl":"10.1177/00220345251334379","url":null,"abstract":"<p><p>Perineural invasion (PNI) frequently occurs in head and neck squamous cell carcinoma (HNSCC), which correlates with poor survival and induces intractable pain and numbness. There is no effective treatment for PNI or associated pain. To gain a better understanding of PNI at the molecular and cellular level, we produced an orthotopic, syngeneic mouse model of PNI by inoculating mouse oral cancer cells into the infraorbital nerve (ION), a nerve that is susceptible to cancer invasion in patients with HNSCC. Mice with PNI in the ION exhibited both evoked and spontaneous nociception and impaired oral function, mimicking human conditions. PNI resulted in a drastic reduction in the proportion and altered mechanical thresholds in mechanically sensitive trigeminal neurons; axon and myelin abnormalities, as well as phagocytic cells, were observed. The tumor bed is marked by CD4<sup>+</sup> and CD8<sup>+</sup> T cells, CD68<sup>+</sup> cells, and F4/80<sup>+</sup> macrophages, while CD4<sup>+</sup>, CD8<sup>+</sup>, and CD68<sup>+</sup> immune cells can be found surrounding the nerve. The intraneural niche is predominantly marked by CD68 that does not overlap with F4/80 but instead overlaps with NF200 and MPZ and occasionally with DAPI, suggesting these are likely phagocytic macrophages or Schwann cells. Finally, our RNA sequencing pathway analysis in mouse and human HNSCC found perturbed pathways in neuroinflammation, mitochondrial dysfunction, and cellular metabolism. Additionally, ION-PNI exhibits nerve degenerative features with perturbed pathways that are observed in Alzheimer, Parkinson, and prion diseases. In conclusion, we report a novel, anatomically relevant in vivo model that could be used to study the cellular and molecular mechanisms of PNI-induced neuropathies. Importantly, we found that PNI resembles neurodegenerative diseases with features of altered sensory transduction and conduction, neuroinflammation, and mitochondrial dysfunction, which may underlie peripheral neuropathies, such as pain.</p>","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":" ","pages":"1352-1360"},"PeriodicalIF":5.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12678856/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144259698","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
R Mahmoud, A Simon, J Luther, J Pothe, Y Du, C Nottmeier, E Okine, S Knauth, M G Lopez, E Bockamp, J Krivanek, A LeBlanc, J Helms, M Amling, M Kaucka, T Schinke, T Koehne, J Petersen
{"title":"Wnt1's Differential Effects on Craniofacial Bone and Tooth Development.","authors":"R Mahmoud, A Simon, J Luther, J Pothe, Y Du, C Nottmeier, E Okine, S Knauth, M G Lopez, E Bockamp, J Krivanek, A LeBlanc, J Helms, M Amling, M Kaucka, T Schinke, T Koehne, J Petersen","doi":"10.1177/00220345251336191","DOIUrl":"10.1177/00220345251336191","url":null,"abstract":"<p><p>The development of craniofacial bones and teeth relies heavily on the Wnt signaling pathway, yet the specific mechanisms and Wnt variants involved remain under continual investigation. Using publicly available single-cell sequencing data from the mouse incisor, we reveal <i>Wnt1</i> expression across dental structures and investigate its role using a <i>Col1a1</i>-dependent <i>Wnt1</i> transgenic mouse model. Inducing <i>Wnt1</i> early on affects craniofacial bone without disturbing tooth development, but prolonged embryonic induction leads to postnatal mortality with osteopetrosis-like bone overgrowth and malformed teeth. While tooth formation was initially unaffected by postnatal <i>Wnt1</i> induction, prolonged activation impaired tooth root formation and odontoblast differentiation, resulting in shortened roots and thinner dentin. Three-dimensional micro-computed tomography quantification reveal that both embryonic and postnatal activation of <i>Wnt1</i> significantly increase neural crest-derived craniofacial bone volume, whereas mesenchymal-derived craniofacial bones are unaffected. Importantly, osteoclastogenesis is suppressed by <i>Wnt1</i> in a dose-dependent manner, revealed through bulk RNA sequencing and in vitro experiments. These findings emphasize the differential effects of <i>Wnt1</i> on bone development based on origin and highlight its role in modulating osteoclast activity, indicating broader implications for craniofacial development and potential therapeutic avenues.</p>","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":" ","pages":"1415-1424"},"PeriodicalIF":5.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12508500/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144201249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
F Aellos, P L Cuevas, K G Harder, J A Grauer, A Ramos, B Liu, J A Helms
{"title":"The Junctional Epithelium Attachment Is Regulated by Wnt Signaling.","authors":"F Aellos, P L Cuevas, K G Harder, J A Grauer, A Ramos, B Liu, J A Helms","doi":"10.1177/00220345251336168","DOIUrl":"10.1177/00220345251336168","url":null,"abstract":"<p><p>The molecular mechanisms mediating barrier functions of the junctional epithelium (JE) are incompletely understood. The aim of this study was to gain mechanistic insights into how reduced Wnt/β-catenin signaling affects the metabolism, turnover, and attachment of JE cells to the tooth surface. A membrane-permeable selective inhibitor of the Wntless protein, C59, was topically delivered to the JE. Wnt pathway suppression was verified by using <i>Axin2<sup>LacZ/+</sup></i> and <i>Axin2Cre<sup>ERT2/+</sup>;</i><i>R26R<sup>mTmG/+</sup></i> strains of mice. Quantitative analyses were carried out at multiple time points to assess mitotic activity, apoptosis, expression of hemidesmosomal attachment proteins, distribution of immune cells, collagen remodeling, and alveolar bone resorption. To complement these studies, Wntless was genetically deleted in osteocalcin-expressing cells, including those in the JE, after which the same quantitative analyses were performed. C59 caused a dose-dependent inhibition in Wnt signaling, which led to reduced mitotic activity and increased apoptosis in the JE. Continued dosing of C59 was accompanied by downregulation of the hemidesmosome attachment proteins laminin 5, plectin, and integrin β4 and a disruption in collagen orientation. A genetic approach in which Wntless function was inhibited in osteocalcin-expressing JE cells yielded similar inhibitory effects on Wnt signaling, mitotic activity, the JE's attachment to the tooth surface, and an increase in immune cells within the connective tissue. Wnt/β-catenin signaling is required for JE homeostasis, and disruptions to the pathway are sufficient to cause JE breakdown and attachment loss. Methods to modulate Wnt/β-catenin signaling may prove beneficial in restoring JE homeostasis after injury or disease.</p>","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":" ","pages":"1405-1414"},"PeriodicalIF":5.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13044411/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144259699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Release of Bisphenol A from Dental Materials: Risks and Future Perspectives.","authors":"A Tichy, T Srolerova, F Schwendicke","doi":"10.1177/00220345251337728","DOIUrl":"10.1177/00220345251337728","url":null,"abstract":"<p><p>The gradual phaseout of dental amalgam has contributed to a significant increase in the use of resin-based materials. While these materials offer several desirable properties, concerns persist regarding their biocompatibility, particularly the release of bisphenol A (BPA). BPA is an endocrine-disrupting chemical linked to adverse effects on human health, including reproductive, developmental, and metabolic disorders. Although food contact materials are the primary source of human BPA exposure and the contribution of dental materials is minor, the associated risks cannot be dismissed due to BPA's nonmonotonic dose-response relationship. In 2023, the European Food Safety Authority proposed a 20,000-fold reduction in the tolerable daily intake of BPA to 0.2 ng/kg body weight, citing immune system effects at extremely low doses. This proposal has sparked regulatory and scientific debate, as adopting such a stringent limit would effectively ban the use of BPA in food contact materials and many other products. Given this context, it is essential to assess the release of BPA from dental materials both in vitro and in vivo. However, data interpretation is complicated by methodological inconsistencies, including variations in material composition, specimen preparation, choice of extraction media, experimental duration, and analytical methods. In addition, pivotal differences in reporting results make it difficult to synthesize findings and draw reliable conclusions. This review examines the controversy surrounding BPA, critically evaluates evidence on its release from dental materials, and explores mitigation strategies. By highlighting gaps in knowledge and proposing future research directions, this review aims to provide clinicians, researchers, and policymakers with a clearer understanding of BPA-related complexities, ultimately contributing to patient safety and material innovation.</p>","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":" ","pages":"1051-1060"},"PeriodicalIF":5.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12301515/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144311113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
L Parisi, F Mansour, S Rihs, I Schnyder, G C La Scala, C Katsaros, M Degen
{"title":"The Skin-to-Mucosa Ratio Defines the Osteogenic Potential of Lip Fibroblasts.","authors":"L Parisi, F Mansour, S Rihs, I Schnyder, G C La Scala, C Katsaros, M Degen","doi":"10.1177/00220345251321806","DOIUrl":"10.1177/00220345251321806","url":null,"abstract":"<p><p>Fibroblasts isolated from discarded lip tissue obtained during cheiloplasty in patients with cleft lip/palate (CLP) show promising osteogenic potential and may be an appealing cell source for autologous bone regeneration. As the lip is a mucocutaneous junction, explant cultures from unseparated lip biopsies produce mesenchymal outgrowths composed of skin- and mucosa-derived fibroblasts. The proportions of the 2 fibroblast populations, however, differ among CLP patients and depend on the morphology of the excised sample, which is unique for each donor. Understanding the osteogenic activities of CLP fibroblast populations with varying skin-to-mucosa ratios is critical for their therapeutic application. We isolated CLP fibroblasts from 10 unseparated lip biopsies and comprehensively evaluated them for their bone differentiation capacities in vitro, demonstrating heterogeneous osteogenic potentials. Because there are no markers that can distinguish skin from mucosa fibroblasts, we used the respective and matching CLP keratinocytes to ascertain the skin-to-mucosa ratio of the 10 specimens. Thus, we found that CLP fibroblasts isolated from biopsies with high skin-to-mucosa ratios had a much higher osteogenic capacity than those derived from biopsies with low skin-to-mucosa ratios. To validate and solidify these findings, we carefully separated skin and mucosa tissues during corrective lip surgery to isolate pure skin and mucosa CLP lip fibroblasts. Indeed, skin had a higher osteogenic potential than their mucosal counterparts did. Furthermore, we discovered that the high osteogenic activity in skin was limited to specific subpopulations of yet unknown identities. Our findings indicate that skin fibroblasts perform better than their mucosal counterparts do, even though both types of fibroblasts can differentiate into bone-forming cells.</p>","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":" ","pages":"1033-1041"},"PeriodicalIF":5.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143665712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
W Thompson, F Cieplik, L Teoh, N Jakubovics, H Benzian
{"title":"Fighting the Antimicrobial Resistance Global Emergency: The Lifesaving Role of Dentistry.","authors":"W Thompson, F Cieplik, L Teoh, N Jakubovics, H Benzian","doi":"10.1177/00220345251324162","DOIUrl":"10.1177/00220345251324162","url":null,"abstract":"","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":" ","pages":"933-935"},"PeriodicalIF":0.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12209544/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143665699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Enhancing Socioeconomic Status Prediction for Cavities: A Hybrid Method.","authors":"A T M Dao, L G Do, N Stormon, H V Nguyen, D H Ha","doi":"10.1177/00220345251324494","DOIUrl":"10.1177/00220345251324494","url":null,"abstract":"<p><p>Socioeconomic status (SES) measures one's access to social resources across various dimensions. Traditionally, studies on SES commonly use principal component analysis (PCA), a data-driven method, to condense these dimensions into components, typically selecting the first component to represent SES. However, PCA may lack specificity for particular outcomes. Decision tree analysis (DTA), a knowledge-driven approach that identifies outcome-specific dimensions, may address PCA's weaknesses but might not comprehensively capture SES. This study hypothesized that combining DTA and PCA to create SES predictors could enhance predictive accuracy more than using PCA alone could. It also explored whether the DTA-PCA combination, incorporating only significant loading indicators (SLIs) of the first component, could simplify SES predictors without compromising predictive accuracy. The study analyzed 12 SES indicators from the Study of Mothers' and Infants' Life Events Affecting Oral Health (SMILE) birth cohort study, involving 2,182 children. Five SES composites were created: 1 solely from DTA-identified indicators and 2 pairs combining values from either the entire first PCA component or SLIs with and without DTA. These composites served as predictors for predicting dental caries in 5 predictive models. Model accuracy was evaluated using root mean squared error with 5-fold cross-validation. SES composites derived from the DTA-PCA combination demonstrated superior predictive accuracy compared with those from the PCA-only approach. By incorporating only SLIs, this hybrid method generated SES predictors that not only outperformed those using the entire first component but also demonstrated noninferiority relative to the DTA-only method. This approach offers a promising framework for developing SES composites to predict dental caries, potentially improving the precision of predictive models. In addition, this method offers a practical framework for creating composite predictors from multi-item measurements across various outcomes. For future research using this method, a 3-step process is recommended: (1) identify relevant items using DTA, (2) determine their weights through PCA, and (3) generate a composite using the SLIs.</p>","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":" ","pages":"947-954"},"PeriodicalIF":5.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12209541/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143660142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Potential of High-Intensity Focused Ultrasound in Enamel Remineralization.","authors":"B Shrestha, S M Rajan, M Saunders, A Fawzy","doi":"10.1177/00220345251323869","DOIUrl":"10.1177/00220345251323869","url":null,"abstract":"<p><p>Remineralization is an essential interventional strategy for intercepting enamel white spot lesions (WSLs). Given the limitations of both natural and/or fluoride-mediated repair processes, there is a need to develop novel strategies for repairing enamel WSLs via a minimally invasive approach while restoring the unique ultrastructural integrity and functional properties. Inspired by the unique capability of high-intensity focused ultrasound (HIFU) in facilitating the crystallization process, we propose a novel strategy of employing HIFU for in vitro repair of WSLs through synergizing the crystallization process required for hydroxyapatite (HAP) formation from its precursor (calcium phosphate ion clusters; CPICs). Following CPIC formulation and characterization including the resultant amorphous calcium phosphate (ACP), the effect of HIFU on the ACP-to-HAP transition on the amorphous substrate was investigated using transmission electron microscopy and high-resolution transmission electron microscopy, selected area electron diffraction, and X-ray diffraction (XRD). The results showed profound amorphous-to-crystalline phase transition, within 5- to 30-min HIFU exposure, whereas the long axis of the resultant HAP corresponded with the (002) plane, and a lattice spacing of 0.34 nm indicated a preferred <i>c</i>-axis growth direction consistent with the orientation of natural enamel crystallites. For enamel repair, artificial WSLs were created on enamel specimens and then subjected to CPICs, followed by HIFU exposure for 2.5, 5, or 10 min. Scanning electron and atomic force microscopies revealed the decreased surface roughness and the gradual obliteration in the WSL porous structure with continuous linear coaxial arrangement of HAP crystallites filling the prismatic/interprismatic gaps closely resembling sound enamel specifically with 5-min HIFU exposure. Enamel WSL ultrastructural repair was further confirmed from XRD and Raman spectral analyses with the associated regaining of mineral density and nanomechanical properties as reflected from micro-computed tomography (CT) and nanoindentation results, respectively. Micro-CT further validated the subsurface remineralization of WSLs with HIFU exposure. Within the same exposure parameters, HIFU exhibited a potent antibiofilm effect against <i>Streptococcus mutans</i>. This study introduced a new approach for remineralizing enamel WSLs through the potent synergy between HIFU and CPICs.</p>","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":" ","pages":"983-992"},"PeriodicalIF":5.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12209549/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143665701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M Takedachi, M Murata, K Sawada, K Kawasaki, K Kawakami, A Sugimoto, C Morimoto, H Sakashita, Y Usami, C Fujihara, T Iwayama, S Murakami
{"title":"Anti-inflammatory Annexin A1 in Periodontitis via Formyl Peptide Receptor 2.","authors":"M Takedachi, M Murata, K Sawada, K Kawasaki, K Kawakami, A Sugimoto, C Morimoto, H Sakashita, Y Usami, C Fujihara, T Iwayama, S Murakami","doi":"10.1177/00220345251322151","DOIUrl":"10.1177/00220345251322151","url":null,"abstract":"<p><p>Although annexin A1 (ANXA1) is known to mediate inflammatory responses through N-formyl peptide receptor 2 (FPR2), the role of the ANXA1-FPR2 signaling pathway in periodontal disease remains unclear. This study investigated the contribution of this pathway to the pathophysiology of periodontal disease. Using a ligature-induced mouse model, we performed histologic analyses to examine ANXA1 and FPR2 expression. We observed upregulation of ANXA1 and FPR2 within the gingiva and periodontal ligament. In vitro analysis of human periodontal ligament cells revealed that interleukin 1β (IL-1β)-induced secretion of IL-8 and granulocyte-macrophage colony-stimulating factor was significantly increased in the presence of WRW4, an FPR2 antagonist. Furthermore, IL-1β-mediated upregulation of IL-8 was significantly enhanced in human periodontal ligament cells by silencing <i>ANXA1</i> and <i>FPR2</i> expression via small interfering RNAs. The effect of the ANXA1-FPR2 signaling pathway on periodontal tissue destruction was also examined in murine periodontitis under daily administration of WRW4 or an ANXA1 N-terminal mimetic peptide, Ac2-26, with micro-computed tomography and histologic analyses. WRW4 administration significantly intensified alveolar bone resorption, increased the number of osteoclasts on the alveolar bone surface, and dilated blood vessels in the periodontal ligament. Conversely, Ac2-26 administration significantly mitigated alveolar bone resorption. Collectively, these findings suggest a role for the ANXA1-FPR2 signaling pathway in attenuating the pathogenesis of periodontal disease by regulating localized inflammatory responses within periodontal tissues.</p>","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":" ","pages":"1014-1021"},"PeriodicalIF":5.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143665697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}