Fanconi anemia (FA) increases the risk of oral potentially malignant disorders (OPMDs) and oral squamous cell carcinoma; however, the stromal alterations associated with FA-related oral lesions remain poorly defined. We investigated whether extracellular matrix (ECM) remodeling represents a quantifiable feature of FA-associated OPMDs. A total of 119 participants were included: controls with normal mucosa or oral leukoplakia (OL) and individuals with FA. Histopathological and immunohistochemical analyses (p53, Ki-67, α-SMA, and elastin), picrosirius red staining, and multiphoton microscopy combining second-harmonic generation and 2-photon fluorescence were performed, complemented by salivary and transcriptomic profiling. Additionally, Fanca-deficient mice were used to assess stromal remodeling. Compared with sporadic OL, FA-OL exhibited reduced collagen density and elastin autofluorescence, a higher collagen-to-elastin ratio, and diminished p53 immunoreactivity. Salivary procollagen type I N-terminal propeptide showed exploratory associations with matrix-derived optical parameters. RNA sequencing of bulk biopsy tissue revealed an altered matrisome transcriptional signature, including enrichment of ECM structural gene sets and downregulation of selected ECM regulatory programs. In FA-related mouse models, collagen and elastin signals were similarly reduced. Collectively, these multimodal data identify ECM disruption as a reproducible feature associated with FA-OL. Matrix disorganization, together with altered epithelial p53 immunoreactivity, supports the hypothesis that epithelial and stromal alterations coexist across the FA-associated oral lesion spectrum.

Titanium alloys based on Ti6Al4V (TA6V) are widely employed as metallic materials for dental implants owing to their overall mechanical and biological performance. However, challenges remain, particularly the mismatch in elastic modulus between the alloy and bone tissue, as well as concerns regarding the potential release of cytotoxic ions such as aluminum (Al) and vanadium (V). Therefore, optimizing alloy composition is crucial to improve peri-implant tissue integration and enhance long-term implant stability. In this in vitro study, the cytocompatibility of a newly developed β-titanium alloy, Ti20Zr3Mo (at%) free of Al and V and exhibiting a reduced elastic modulus compared to that of TA6V, was evaluated using primary human gingival fibroblasts, representative of peri-implant soft tissues. The experimental alloy was compared to conventional TA6V and commercially pure titanium (Cp-Ti40). Several endpoints were investigated to characterize cell-material interactions. Cell viability and cytotoxicity were analyzed by Live/Dead fluorescence staining, while metabolic activity was assessed using the Alamar Blue assay. Cell adhesion and surface colonization were observed through scanning electron microscopy and confocal laser imaging. In addition, extracellular matrix production, including collagen deposition, was examined to evaluate the potential for soft tissue integration. Results demonstrated that Ti20Zr3Mo alloy supported comparable cell viability to Cp-Ti40 while exhibiting enhanced surface colonization by fibroblasts. These findings suggest that the substitution of Al and V with Zr and Mo in specific proportions may promote suitable fibroblast-Ti-alloy interactions, which could improve peri-implant soft tissue sealing and contribute to the long-term success of dental implants. This work highlights a promising strategy for developing next-generation titanium alloys that combine improved biological responses with suitable mechanical properties, with the ultimate goal of enhancing the long-term clinical performance of dental implants.

GLP-1RAs (glucagon-like peptide-1 receptor agonists) have become one of the fastest-growing drug classes worldwide, with prescriptions for obesity treatment increasing by 587% from 2019 to 2024. While their metabolic and cardiovascular benefits are well established, the implications for oral health remain largely unexamined. Preclinical evidence consistently demonstrates anti-inflammatory and osteoprotective effects on periodontal and peri-implant tissues: GLP-1RAs promote osteogenic differentiation of periodontal ligament stem cells, reduce alveolar bone resorption in animal models of periodontitis, and enhance implant osseointegration in diabetic rats. However, these findings are based exclusively on in vitro and animal studies, with only a single retrospective cohort study providing limited clinical data. Conversely, several oral adverse effects have been reported based on pharmacovigilance analyses, including xerostomia, dysgeusia, and anosmia, particularly for semaglutide. Gastrointestinal side effects, particularly nausea (15% to 50%), vomiting (5% to 24%), and gastroesophageal reflux, pose a plausible but unquantified risk for tooth erosion and secondary caries. A bidirectional link between GLP-1 signaling and the oral microbiota, mediated by bacterial dipeptidyl peptidase (DPP)-4-like enzymes that degrade endogenous GLP-1, adds further complexity. Despite this breadth of potential interactions, no prospective study has used any dental outcome as an endpoint in patients receiving GLP-1RAs. This critical appraisal synthesizes the evidence across multiple dental disciplines, grades it in each domain, and identifies the gaps that demand urgent investigation.

Periodontal nerves, comprising sensory, sympathetic, and parasympathetic fibers, are essential components of the periodontium. Beyond their classic sensory and proprioceptive functions, these neural networks actively modulate periodontal immune responses, bone remodeling, and tissue regeneration. They orchestrate tissue homeostasis by releasing specific neuropeptides, neurotransmitters, and neurotrophic factors. The progression of periodontitis is intimately linked to neural dysregulation, where proinflammatory mediators (e.g., excessive substance P and sympathetic catecholamines) overpower protective signals (e.g., calcitonin gene-related peptide and parasympathetic acetylcholine). Conversely, successful periodontal regeneration requires the restoration of this neural equilibrium. Nerve terminals rapidly sprout into osteogenic zones during early repair. Subsequently, their spatiotemporally patterned signaling suppresses osteoclastogenesis and promotes the osteogenic differentiation of stem cells. Crucially, these local neural networks function as a bidirectional conduit linking the periodontium to the central nervous system: systemic stressors (eg, sleep deprivation and chronic stress) can compromise ganglionic autophagy or trigeminal function to exacerbate periodontal bone loss, while periodontal pathogens can reciprocally exploit these pathways to induce central neuroinflammation. Recognizing this interconnected oral-neural-brain axis not only explains why certain periodontitis-susceptible patients remain refractory to conventional therapies but also highlights the broader impact of periodontal inflammation on neurodegenerative risk. Furthermore, nerve-targeted strategies, including neurotrophin-functionalized biomaterials, local neuropeptide delivery, and bioelectric neuromodulation, offer promising approaches to resolving refractory inflammation, restoring periodontal integrity, and concurrently mitigating the risk of associated central neuroinflammation. In this review, we comprehensively characterize the spatiotemporal plasticity of periodontal nerves under physiological and pathological conditions. We dissect the molecular mechanisms linking neural signaling to periodontal immunity and repair, and highlight how integrating neurobiology into periodontology could advance the development of next-generation regenerative medicine.

Cleft palate can be caused by failure of elevation of the palatal shelves over the tongue during development. The physical mechanism of elevation is poorly understood. It is thought that elevation is obstructed by the tongue in a condition known as Pierre Robin sequence (PRS), in which the mandible is smaller (micrognathia) and/or further back than normal (retrognathia). Some PRS cases are associated with mutations in the regulatory and coding regions of SOX9. Here, we first examined the timing of palatal shelf elevation in mouse embryonic explants. While elevation in vivo occurs between embryonic days E13.5 and E14.5, we found that palate elevation occurred in both E12.5 and E13.5 explants immediately upon dissection, indicating release of elastic prestress by removal of the tongue. These findings suggest that palatal shelves are programmed ab initio to grow horizontally (as they do in birds and most reptiles) but are deflected in mammals by the tongue. Next, to examine this process in utero, we generated a new mtHand2[Cre] mouse line to delete Sox9 or to express diphtheria toxin specifically in the mandibular mesenchyme. Sox9 deletion resulted in a hypoplastic, dysmorphic, retrognathic mandible with fully penetrant, complete cleft of the secondary palate. In contrast, most R26R[DTA/+];mtHand2[Cre] embryos showed a reduced mandible (micrognathia) but also displayed a dramatically smaller tongue (microglossia). With a nonobstructing tongue, these mutants exhibited horizontal palatal shelf growth and formed a normal palate. These results are consistent with a mechanism in which physical obstruction by the tongue is the primary cause of downward development of the palatal shelves, far earlier than previously appreciated, and that normal elevation occurs by the release of elastic prestress. We experimentally demonstrate that in PRS, micrognathia causes cleft palate through tongue malpositioning that prevents release of this palatal shelf prestress.

Dentin, the primary structural component of teeth, is a mineralized tissue formed by odontoblasts, which strongly express the Dmp1 gene. Dmp1 is also expressed in osteocytes, making it a valuable marker for studying bone biology and diseases. Transgenic mouse lines expressing Cre, CreER, or fluorescent reporters such as GFP under the control of 8-kb or 10-kb Dmp1 promoters have been widely used to investigate gene functions in odontoblasts and osteocytes. However, the transgenic models exhibit ectopic expression, and reporter signals are often reduced in mature odontoblasts, limiting their utility for lineage tracing and studies of terminal differentiation. To address these limitations, we generated 2 novel knock-in mouse lines, Dmp1[CreERT2] and Dmp1[ZsGreen], using CRISPR-Cas9-mediated genome editing. In both models, an internal ribosome entry site (IRES)-CreERT2 or IRES-ZsGreen cassette was inserted into the 3' untranslated region (UTR) of the endogenous Dmp1 locus. This design preserves normal Dmp1 expression while permitting robust, Dmp1-specific expression of CreERT2 or ZsGreen in odontoblasts and cementoblast/cementocytes. By maintaining endogenous regulatory control, these knock-in lines eliminate the ectopic transgene expression commonly observed in transgenic mice generated by injecting the promoter-driven constructs. The Dmp1[ZsGreen] line enables direct visualization of Dmp1-expressing odontoblasts and cementoblasts/cementocytes, while the Dmp1[CreERT2] line allows inducible genetic manipulation in these cells in vivo. Together, these models provide faithful tools for investigating the cellular and molecular mechanisms regulating dentinogenesis and osteocyte biology, as well as for studying dental and alveolar bone tissues, with potential applications in craniofacial biology.

Growing evidence supports a strong association between periodontitis and Alzheimer's disease (AD), yet the mechanisms linking these conditions remain poorly defined. In neurodegenerative disorders, including AD, microglia are often characterized by increased accumulation of lipid droplets (LD), heightened activation, and impaired function. In this study, we examined whether Porphyromonas gingivalis (Pg), a keystone periodontal pathogen, promotes LD accumulation in microglia and disrupts their function. We found that infection with Pg (ATCC 33277) induces robust LD accumulation in BV2 microglial cells and in microglia from Pg-infected App knock-in mice. This Pg-driven LD buildup was closely associated with elevated reactive oxygen species (ROS) production, impaired phagocytic ability, and altered activation. Notably, pharmacologic inhibition of LD with a long-chain fatty acyl-CoA synthetase inhibitor effectively reversed Pg-induced LD accumulation, mitigated ROS production, and restored phagocytic function, thus underscoring the critical role of lipid metabolism in regulating microglial function. These findings support a model in which, in the context of periodontitis, systemic dissemination of periodontal pathogens and inflammatory mediators promotes LD accumulation in microglia, and this metabolic alteration exacerbates microglia dysfunction via a self-reinforcing cycle of excessive oxidative stress and impaired phagocytosis, potentially accelerating AD progression.

Patient-centered care is central to high-quality health care, yet systems-level understanding of how patients themselves define dental care quality remains limited. This systematic review synthesized qualitative evidence using the Donabedian framework to examine patients' perceptions of dental care and to identify core elements of quality as defined by the patients themselves. A comprehensive search of 6 databases was conducted up to July 2025. Qualitative and mixed-methods studies examining patients' views, experiences, and values related to dental care delivery were included. Study quality was appraised using the Joanna Briggs Institute Critical Appraisal tool, and data were synthesized using thematic synthesis. Thirty-six studies spanning diverse populations and dental care contexts were included. Four analytical themes characterized how patients define quality dental care: (1) organizational and structural conditions shaping confidence in dental care; (2) feeling safe in experienced hands, reflecting perceived clinical competence; (3) interpersonal care as the foundation of perceived quality, encompassing respect, empathy, communication, and shared decision-making; and (4) relational continuity as a patient-relevant outcome over time. Patients interpret relational, emotional, and systemic features of care as symbolic indicators of health system orientation, particularly in contexts in which technical competence is difficult to assess. These indicators accumulate across encounters, shaping expectations of future care and influencing engagement, particularly among populations at greater risk of disengagement, highlighting the centrality of relational and organizational dimensions in patient-defined dental care quality.

Periodontitis affects more than 1 billion people worldwide but remains largely underdiagnosed. The oral microbiota offers a noninvasive diagnostic window, but studies based on 16S rRNA data have reported heterogeneous and often suboptimal performance. It remains unclear which oral habitat and modeling strategy best support clinical decision making. We analyzed 2,303 adult samples from 33 publicly available 16S rRNA V3-V4 Illumina projects encompassing saliva, supragingival, and subgingival habitats. Amplicon sequence variants (ASVs) were identified against the expanded Human Oral Microbiome Database. Compact microbial signatures were identified through multivariate techniques (sparse partial least squares discriminant analysis and a customized genetic algorithm). Five machine-learning algorithms were benchmarked under repeated cross-validation and test-set evaluation. Diagnostic performance was assessed using the area under the receiver-operating characteristic curve (AUC), and clinical net benefit was assessed using decision curve analysis (DCA). Generalized additive models (GAMs) provided the best discrimination with compact panels of 6 to 12 ASVs. Saliva and supragingival achieved the best discrimination (AUC = 0.928 and 0.903; sensitivity = 92.4% and 87.6%; specificity = 85.3% and 81.7%), significantly outperforming subgingival plaque (0.803, 78.2% and 75.1%, respectively; adjusted P ≤ 0.001). DCA further demonstrated the highest and most stable net clinical benefit in saliva (AUC-DCA = 0.437), followed by supragingival (0.419) and subgingival (0.331). Forty-eight taxonomically annotated ASVs emerged as predictors, underscoring the models' biological interpretability. In subgingival sites, the most prevalent features were health-associated commensals, such as Streptococcus oralis subsp. dentisani. Supragingival plaque and saliva predominantly revealed periodontitis-associated taxa, including Porphyromonas gingivalis and Filifactor alocis. Thus, saliva and supragingival plaque better capture the microbial fingerprint of periodontitis-associated dysbiosis. Oral microbiome-based models across habitats showed consistent diagnostic performance for periodontitis. The GAM algorithm with compact, interpretable microbial signatures achieved strong discrimination and superior net benefit in saliva and supragingival samples, highlighting its potential for translation into scalable, noninvasive diagnostic tools for precision periodontics.

The objective of this study was to investigate if poor oral health mediates income losses over a 12-y follow-up period in Australian adults. Data were obtained from adults aged ≤65 y, selected to minimize the influence of retirement, who participated in both waves (2004-2006 and 2017-2018) of the National Study of Adult Oral Health (NSAOH), nationally representative surveys of Australians aged ≥15 y. Baseline household income, categorized as low (<A$40,000), medium (A$40,000-A$80,000), or high (>A$80,000), was the exposure, and follow-up household income was the outcome, which was inflation-adjusted using the Consumer Price Index (CPI) to ensure comparability across both waves and account for changes in purchasing power over time. Change in self-reported oral health, categorized as "good" (excellent/very good/good at both waves) or "poor" (persistently poor or declined to poor), was examined as a mediator. Marginal structural models using multinomial logistic regression and inverse probability weighting estimated indirect (mediated) effects of poor oral health on income loss, adjusting for sociodemographic and behavioral confounders. Missing data were handled using multiple imputation, and E-values assessed robustness to unmeasured confounding. A total of 707 adults were included (mean [SD] age at baseline: 41.4 [8.17] y; males: 40.6%). At baseline, 19.6%, 46.7%, and 33.7% reported low, medium, and high income, respectively, and 15% reported poor oral health. Compared to high baseline income, individuals with medium income had a 3.10 times higher risk of shifting to low income (vs. high income) at follow-up, with poor oral health mediating 5% to 7% of this effect. The population-attributable fraction for the mediated effect was 2.1%, equivalent to approximately 376,932 Australian adults whose income decline may be partly explained by deteriorating oral health. Poor oral health partially mediated long-term income decline among Australian adults, underscoring the sustained economic burden of oral health inequalities.

Excessive osteoclast activation drives rapid subchondral bone destruction, serving as a critical early-stage event precipitating temporomandibular joint osteoarthritis (TMJ-OA). Although epigenetic remodeling is widely recognized as an important interface between pathological environmental signals and genomic response, the specific epigenetic mechanisms translating TMJ-OA-associated stimulation into pathological osteoclast activation remain to be elucidated. Here, using a mechanically induced TMJ-OA mouse model, we identify aberrant reactive oxygen species (ROS) accumulation as a critical upstream driver initiating excessive osteoclast activation and subsequent joint deterioration. By integrating transcriptomic and epigenomic analyses, we delineate the chromatin remodeler AT-rich interaction domain 1A (ARID1A) as an essential oxidative stress sensor within the osteoclast lineage. Mechanistically, ROS accumulation induces ARID1A upregulation and recruitment to the Src enhancer, transcriptionally activating Src and amplifying PI3K-AKT signaling to drive pathological osteoclastogenesis. Conditional knockout of Arid1a in myeloid cells effectively abrogates subchondral bone loss and cartilage destruction in TMJ-OA. Translating these mechanistic insights, we engineered an ROS-responsive, osteoclast-targeting hydrogel for the on-demand delivery of an ARID1A-dependent canonical BRG1/BRM-associated factor complex inhibitor, which successfully alleviates TMJ-OA progression. Our findings establish the epigenetic response to ROS accumulation as a key pathogenic mechanism in TMJ-OA and highlight ARID1A as a promising therapeutic target for early disease intervention.

Traumatic life events may shape how individuals utilize health care, yet their impact on medical and dental service utilization is underexplored. This study investigates how such events influence subsequent health care use. We analyzed data from the Mexican Health and Aging Study, the first longitudinal cohort in Mexico of middle-aged and older adults. The analytic sample comprised 17,424 unique individuals across 39,875 total observations. Three traumatic events were examined in relation to their effects on medical and dental service use: (1) experience of a natural disaster, (2) experience of the death of a child, and (3) experience of a crime or accident. We combined propensity score weighting with multivariable mixed-effects logistic regression to account for both confounding and correlation arising from repeated measures. We estimated the effect of exposure to each traumatic event by parametric g-computation, calculating risk differences with 95% confidence intervals (CIs). Exposure to a natural disaster increased medical service use by 4.2% (95% CI, 2.2 to 6.2) while reducing utilization of dental care by 4.8% (95% CI, -7.0 to -2.5). The death of a child increased medical service use by 4.9% (95% CI, 2.7 to 7.2) while reducing utilization of dental care by 6.0% (95% CI, -8.6 to -3.4). Crime or accidents increased utilization of medical services by 12.7% (95% CI, 11.1 to 14.2) while having no clear effect on utilization of dental care. Traumatic events have substantial and differential impacts on health care utilization. In particular, among middle-aged and older adults in Mexico, natural disasters and the death of a child have divergent effects on the utilization of medical versus dental care, while crime and accidents only affect medical care. Future research into this underdeveloped area may help to develop a more precise understanding of the underlying mechanisms.

The entire vertebrate facial skeleton is derived from Hox-negative cranial neural crest cells (CNCCs) that populate the embryonic frontonasal prominence and the first pharyngeal arches. Previous studies have shown that the Edn1/Ednra-Dlx5/Dlx6-Hand2 regulatory network specifies the maxillomandibular identity of CNCCs in the first pharyngeal arches in mice and that the combined application of retinoic acid and noggin to the presumptive maxillary domain in avian embryos transformed maxillary tissues to frontonasal structures, but the molecular mechanisms regulating frontonasal CNCC identity remain unresolved. Biallelic loss of function of any of the aristaless-like homeobox genes, including ALX1, ALX3, and ALX4, which exhibit partly overlapping patterns of expression in the frontonasal CNCCs, causes frontonasal dysplasia. In this study, we show that mice with combined inactivation of Alx1 and Alx3 throughout CNCCs exhibit disruption of frontonasal CNCC identity with ectopic activation of maxillary CNCC developmental profiles. We show that transgenic Alx1 expression throughout the CNCCs, starting from when they were migrating toward the facial primordia, caused ectopic activation of frontonasal CNCC marker genes and suppression of the maxillomandibular marker genes in the developing maxillary and mandibular processes and resulted in the formation of duplicated premaxilla at the expense of maxillary structures. These data identify the ALX transcription factors as key regulators specifying frontonasal CNCC identity and fill a long-standing gap in the molecular mechanism patterning the regional identities of the CNCC-derived craniofacial mesenchyme.

Abnormal enamel mineralization has been reported in genetic conditions associated with hypocalcemia but never with hypercalcemia. In the present study, we report 10 patients from 2 unrelated families in whom hypomineralized enamel co-segregated with hypercalcemia due to a complete deletion or frameshifting premature truncation (p.(Ser18Argfs*2)) of the guanine nucleotide-binding protein (G-protein) subunit α11 (GNA11) gene. Both GNA11 variants were heterozygous and predicted to cause a loss of function of Gα11. Multiproxy imaging analyses of naturally exfoliated primary teeth and clinically extracted permanent teeth from 2 affected patients revealed abnormal enamel mineralization, with constitutive patches of hypomineralization following no set pattern. In parallel, the study of wild-type mouse tooth germs using combined molecular and protein analyses showed Gna11 and Gα11 protein expression in ameloblasts at the secretion and maturation stages, as well as in odontoblasts, suggesting a role for Gα11 in tooth formation. Furthermore, the analysis of a mouse model of Familial Hypocalciuric Hypercalcemia 2 (FHH2) revealed delayed onset of enamel mineralization in the continuously growing incisors and hypomineralized enamel in both incisor and molars of heterozygous (Gna11Tm1b[+/-]) mice, with defects that are very similar to those affecting human FHH2 teeth. In conclusion, our study reveals that abnormal enamel mineralization may occur in association with hypercalcemia due to loss-of-function GNA11 mutations, opening a new field of investigation and highlighting the need to include a dentist in the multidisciplinary team in charge of patients with monogenic calcium disorders.

Periodontitis is a chronic inflammatory disease characterized by dysregulated neutrophil responses that contribute to progressive periodontal tissue destruction. Here, we observed aberrant fibrin accumulation in inflamed periodontal tissues and hypothesized that fibrin acts as a pathogenic mediator that promotes neutrophil recruitment and activation, thereby triggering neutrophil extracellular traps (NETs) formation and reactive oxygen species (ROS) production. To therapeutically target fibrin deposition, we developed a ROS-responsive hydrogel (PVHA@tPA) that enables localized delivery of tissue plasminogen activator (tPA), activating plasminogen to mediate fibrin degradation. In vitro, tPA released from the hydrogel degraded fibrin matrices in the presence of plasminogen, which restrained fibrin-mediated neutrophil adhesion and migration while suppressing subsequent NETs formation and ROS overproduction. By attenuating this neutrophil overactivation, the treatment improved the osteogenic capacity of periodontal ligament stem cells (PDLSCs) and the angiogenic potential of human umbilical vein endothelial cells (HUVECs). In vivo, PVHA@tPA treatment in a mouse periodontitis model reduced gingival fibrin deposition, attenuated neutrophil-associated inflammation, downregulated proinflammatory factors, and alleviated alveolar bone loss. Together, these findings identify fibrin deposition as a key driver of neutrophil dysregulation in periodontitis and establish fibrin-targeted therapy as a promising strategy to rebalance neutrophil responses and ameliorate periodontitis.