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Proceedings of the National Academy of... Dec 2022The outstanding mechanical and chemical properties of dental enamel emerge from its complex hierarchical architecture. An accurate, detailed multiscale model of the...
The outstanding mechanical and chemical properties of dental enamel emerge from its complex hierarchical architecture. An accurate, detailed multiscale model of the structure and composition of enamel is important for understanding lesion formation in tooth decay (dental caries), enamel development (amelogenesis) and associated pathologies (e.g., amelogenesis imperfecta or molar hypomineralization), and minimally invasive dentistry. Although features at length scales smaller than 100 nm (individual crystallites) and greater than 50 µm (multiple rods) are well understood, competing field of view and sampling considerations have hindered exploration of mesoscale features, i.e., at the level of single enamel rods and the interrod enamel (1 to 10 µm). Here, we combine synchrotron X-ray diffraction at submicrometer resolution, analysis of crystallite orientation distribution, and unsupervised machine learning to show that crystallographic parameters differ between rod head and rod tail/interrod enamel. This variation strongly suggests that crystallites in different microarchitectural domains also differ in their composition. Thus, we use a dilute linear model to predict the concentrations of minority ions in hydroxylapatite (Mg and CO/Na) that plausibly explain the observed lattice parameter variations. While differences within samples are highly significant and of similar magnitude, absolute values and the sign of the effect for some crystallographic parameters show interindividual variation that warrants further investigation. By revealing additional complexity at the rod/interrod level of human enamel and leaving open the possibility of modulation across larger length scales, these results inform future investigations into mechanisms governing amelogenesis and introduce another feature to consider when modeling the mechanical and chemical performance of enamel.
Topics: Humans; Dental Caries; Crystallography; Amelogenesis Imperfecta; Amelogenesis; Dental Enamel
PubMed: 36534796
DOI: 10.1073/pnas.2211285119 -
International Journal of Molecular... Apr 2023Heat shock proteins (HSPs) are a class of molecular chaperones with expression increased in response to heat or other stresses. HSPs regulate cell homeostasis by... (Review)
Review
Heat shock proteins (HSPs) are a class of molecular chaperones with expression increased in response to heat or other stresses. HSPs regulate cell homeostasis by modulating the folding and maturation of intracellular proteins. Tooth development is a complex process that involves many cell activities. During tooth preparation or trauma, teeth can be damaged. The damaged teeth start their repair process by remineralizing and regenerating tissue. During tooth development and injury repair, different HSPs have different expression patterns and play a special role in odontoblast differentiation and ameloblast secretion by mediating signaling pathways or participating in protein transport. This review explores the expression patterns and potential mechanisms of HSPs, particularly HSP25, HSP60 and HSP70, in tooth development and injury repair.
Topics: Heat-Shock Proteins; Molecular Chaperones; HSP70 Heat-Shock Proteins; Odontogenesis; HSP90 Heat-Shock Proteins
PubMed: 37108621
DOI: 10.3390/ijms24087455 -
Journal of Structural Biology Dec 2021During enamel formation, the organic enamel protein matrix interacts with calcium phosphate minerals to form elongated, parallel, and bundled enamel apatite crystals of... (Review)
Review
During enamel formation, the organic enamel protein matrix interacts with calcium phosphate minerals to form elongated, parallel, and bundled enamel apatite crystals of extraordinary hardness and biomechanical resilience. The enamel protein matrix consists of unique enamel proteins such as amelogenin, ameloblastin, and enamelin, which are secreted by highly specialized cells called ameloblasts. The ameloblasts also facilitate calcium and phosphate ion transport toward the enamel layer. Within ameloblasts, enamel proteins are transported as a polygonal matrix with 5 nm subunits in secretory vesicles. Upon expulsion from the ameloblasts, the enamel protein matrix is re-organized into 20 nm subunit compartments. Enamel matrix subunit compartment assembly and expansion coincide with C-terminal cleavage by the MMP20 enamel protease and N-terminal amelogenin self-assembly. Upon enamel crystal precipitation, the enamel protein phase is reconfigured to surround the elongating enamel crystals and facilitate their elongation in C-axis direction. At this stage of development, and upon further amelogenin cleavage, central and polyproline-rich fragments of the amelogenin molecule associate with the growing mineral crystals through a process termed "shedding", while hexagonal apatite crystals fuse in longitudinal direction. Enamel protein sheath-coated enamel "dahlite" crystals continue to elongate until a dense bundle of parallel apatite crystals is formed, while the enamel matrix is continuously degraded by proteolytic enzymes. Together, these insights portrait enamel mineral nucleation and growth as a complex and dynamic set of interactions between enamel proteins and mineral ions that facilitate regularly seeded apatite growth and parallel enamel crystal elongation.
Topics: Ameloblasts; Amelogenesis; Amelogenin; Animals; Apatites; Calcium; Calcium Phosphates; Crystallization; Dental Enamel; Dental Enamel Proteins; Humans; Microscopy, Electron; Minerals
PubMed: 34748943
DOI: 10.1016/j.jsb.2021.107809 -
Journal of Dental Research Dec 2021The nanofibrous nature and its intricate structural organization are the basis for the extraordinary ability of sound enamel to outlive masticatory forces at minimal... (Review)
Review
The nanofibrous nature and its intricate structural organization are the basis for the extraordinary ability of sound enamel to outlive masticatory forces at minimal failure rates. Apatite nanofibers of several hundreds of micrometers to possibly millimeters in length originate during the secretory stage of amelogenesis as 2-nm-thin and 15-nm-wide ribbons that develop and grow in length under the guidance of a dynamic mixture of specialized proteins, the developing enamel matrix (DEM). A critical role in the unidirectional and oriented growth of enamel mineral ribbons has been attributed to amelogenin, the major constituent of the DEM. This review elaborates on recent studies on the ability of ribbon-like assemblies of amelogenin to template the formation of an amorphous calcium phosphate precursor that transforms into apatite mineral ribbons similar to the ones observed in developing enamel. A mechanistic model of the biological processes that drive biomineralization in enamel is presented in the context of a comparative analysis of enamel mouse models and earlier structural data of the DEM emphasizing a regulatory role of the matrix metalloproteinase 20 in mineral deposition and the involvement of a process-directing agent for the templated mineral growth directed by amelogenin nanoribbons.
Topics: Amelogenesis; Amelogenin; Animals; Dental Enamel; Dental Enamel Proteins; Matrix Metalloproteinase 20; Mice; Nanotubes, Carbon
PubMed: 34009057
DOI: 10.1177/00220345211012925 -
International Journal of Oral Science Mar 2023Tooth germ injury can lead to abnormal tooth development and even tooth loss, affecting various aspects of the stomatognathic system including form, function, and...
Tooth germ injury can lead to abnormal tooth development and even tooth loss, affecting various aspects of the stomatognathic system including form, function, and appearance. However, the research about tooth germ injury model on cellular and molecule mechanism of tooth germ repair is still very limited. Therefore, it is of great importance for the prevention and treatment of tooth germ injury to study the important mechanism of tooth germ repair by a tooth germ injury model. Here, we constructed a Tg(dlx2b:Dendra2-NTR) transgenic line that labeled tooth germ specifically. Taking advantage of the NTR/Mtz system, the dlx2b tooth germ cells were depleted by Mtz effectively. The process of tooth germ repair was evaluated by antibody staining, in situ hybridization, EdU staining and alizarin red staining. The severely injured tooth germ was repaired in several days after Mtz treatment was stopped. In the early stage of tooth germ repair, the expression of phosphorylated 4E-BP1 was increased, indicating that mTORC1 is activated. Inhibition of mTORC1 signaling in vitro or knockdown of mTORC1 signaling in vivo could inhibit the repair of injured tooth germ. Normally, mouse incisors were repaired after damage, but inhibition/promotion of mTORC1 signaling inhibited/promoted this repair progress. Overall, we are the first to construct a stable and repeatable repair model of severe tooth germ injury, and our results reveal that mTORC1 signaling plays a crucial role during tooth germ repair, providing a potential target for clinical treatment of tooth germ injury.
Topics: Animals; Mice; Mechanistic Target of Rapamycin Complex 1; Signal Transduction; Tooth; Tooth Germ; Odontogenesis
PubMed: 36927863
DOI: 10.1038/s41368-023-00218-3 -
Journal of Structural Biology Dec 2021The revolution in genetics has rapidly increased our knowledge of human and mouse genes that are critical for the formation of dental enamel and helps us understand how... (Review)
Review
The revolution in genetics has rapidly increased our knowledge of human and mouse genes that are critical for the formation of dental enamel and helps us understand how enamel evolved. In this graphical review we focus on the roles of 41 genes that are essential for the secretory stage of amelogenesis when characteristic enamel mineral ribbons initiate on dentin and elongate to expand the enamel layer to the future surface of the tooth. Based upon ultrastructural analyses of genetically modified mice, we propose a molecular model explaining how a cell attachment apparatus including collagen 17, α6ß4 and αvß6 integrins, laminin 332, and secreted enamel proteins could attach to individual enamel mineral ribbons and mold their cross-sectional dimensions as they simultaneously elongate and orient them in the direction of the retrograde movement of the ameloblast membrane.
Topics: Ameloblasts; Amelogenesis; Animals; Collagen; Dental Enamel; Dental Enamel Proteins; Humans; Integrins; Laminin; Mice; Microscopy, Electron, Scanning; Models, Genetic
PubMed: 34715329
DOI: 10.1016/j.jsb.2021.107805 -
Head and Neck Pathology Jun 2022Primordial odontogenic tumor (POT) is a rare, mixed odontogenic neoplasm composed of spindled and stellate-shaped cells in myxoid stroma resembling dental papilla,...
Primordial odontogenic tumor (POT) is a rare, mixed odontogenic neoplasm composed of spindled and stellate-shaped cells in myxoid stroma resembling dental papilla, surfaced by cuboidal-to-columnar odontogenic epithelium. Most POTs present in the posterior mandible as a well-demarcated radiolucency associated with a developing tooth in children and adolescents. POT is treated conservatively with no recurrences documented to-date. To describe the clinicopathological features of a recurrent POT. A 19-year-old female presented with an asymptomatic swelling, and panoramic radiograph revealed a multiloculated radiolucency in the mandibular body and ramus, with buccal and lingual perforation. The tumor was composed of plump spindle and stellate cells in a delicately collagenous and myxoid stroma, surfaced by columnar epithelial cells with reverse nuclear polarization. There was extensive epithelial proliferation forming invaginations within the tumor mass and organoid/enamel organ-like structures with enameloid-like deposits, dentinoid, and dystrophic calcifications. This was similar to the POT that had been excised four years prior from the same location. The patient underwent hemi-mandibulectomy and currently is free of disease at a thirteen-month follow-up. This report describes the first recurrent POT exhibiting extensive epithelial proliferation.
Topics: Adolescent; Adult; Child; Epithelium; Female; Humans; Mandible; Odontogenic Tumors; Young Adult
PubMed: 34224080
DOI: 10.1007/s12105-021-01354-0 -
Biomolecules Mar 2024Pulpitis is a common and frequent disease in dental clinics. Although vital pulp therapy and root canal treatment can stop the progression of inflammation, they do not... (Review)
Review
Pulpitis is a common and frequent disease in dental clinics. Although vital pulp therapy and root canal treatment can stop the progression of inflammation, they do not allow for genuine structural regeneration and functional reconstruction of the pulp-dentin complex. In recent years, with the development of tissue engineering and regenerative medicine, research on stem cell-based regenerative endodontic therapy (RET) has achieved satisfactory preliminary results, significantly enhancing its clinical translational prospects. As one of the crucial paracrine effectors, the roles and functions of exosomes in pulp-dentin complex regeneration have gained considerable attention. Due to their advantages of cost-effectiveness, extensive sources, favorable biocompatibility, and high safety, exosomes are considered promising therapeutic tools to promote dental pulp regeneration. Accordingly, in this article, we first focus on the biological properties of exosomes, including their biogenesis, uptake, isolation, and characterization. Then, from the perspectives of cell proliferation, migration, odontogenesis, angiogenesis, and neurogenesis, we aim to reveal the roles and mechanisms of exosomes involved in regenerative endodontics. Lastly, immense efforts are made to illustrate the clinical strategies and influencing factors of exosomes applied in dental pulp regeneration, such as types of parental cells, culture conditions of parent cells, exosome concentrations, and scaffold materials, in an attempt to lay a solid foundation for exploring and facilitating the therapeutic strategy of exosome-based regenerative endodontic procedures.
Topics: Regenerative Endodontics; Exosomes; Dental Pulp; Regeneration; Regenerative Medicine
PubMed: 38540750
DOI: 10.3390/biom14030330 -
Research Square Sep 2023BMP2 signaling plays a pivotal role in odontoblast differentiation and maturation during odontogenesis. Teeth lacking Bmp2 exhibit a morphology reminiscent of...
BMP2 signaling plays a pivotal role in odontoblast differentiation and maturation during odontogenesis. Teeth lacking Bmp2 exhibit a morphology reminiscent of dentinogenesis imperfecta (DGI), associated with mutations in dentin matrix protein 1 (DMP1) and dentin sialophosphoprotein (DSPP) genes. Mechanisms by which BMP2 signaling influences expressions of DSPP and DMP1 and contributes to DGI remain elusive. To study the roles of BMP2 in dentin development, we generated Bmp2 conditional knockout (cKO) mice. Through a comprehensive approach involving RNA-seq, immunohistochemistry, promoter activity, ChIP, and Re-ChIP, we investigated downstream targets of Bmp2. Notably, the absence of Bmp2 in cKO mice led to dentin insufficiency akin to DGI. Disrupted Bmp2 signaling was linked to decreased expression of Dspp and Dmp1, as well as alterations in intracellular translocation of transcription factors Dlx3 and Sp7. Intriguingly, upregulation of Dlx3, Dmp1, Dspp, and Sp7, driven by BMP2, fostered differentiation of dental mesenchymal cells and biomineralization. Mechanistically, BMP2 induced phosphorylation of Dlx3, Sp7, and histone acetyltransferase GCN5 at Thr and Tyr residues, mediated by Akt and Erk kinases. This phosphorylation facilitated protein nuclear translocation, promoting interactions between Sp7 and Dlx3, as well as with GCN5 on Dspp and Dmp1 promoters. The synergy between Dlx3 and Sp7 bolstered transcription of Dspp and Dmp1. Notably, BMP2-driven GCN5 acetylated Sp7 and histone H3, while also recruiting RNA polymerase II to Dmp1 and Dspp chromatins, enhancing their transcriptions. Intriguingly, BMP2 suppressed the expression of histone deacetylases. we unveil hitherto uncharted involvement of BMP2 in dental cell differentiation and dentine development through pAkt/pErk42/44/Dlx3/Sp7/GCN5/Dspp/Dmp1.
PubMed: 37790473
DOI: 10.21203/rs.3.rs-3299295/v1 -
International Journal of Molecular... Nov 2022The tooth-periodontium complex and its nerves have active reciprocal regulation during development and homeostasis. These effects are predominantly mediated by a range... (Review)
Review
The tooth-periodontium complex and its nerves have active reciprocal regulation during development and homeostasis. These effects are predominantly mediated by a range of molecules secreted from either the nervous system or the tooth-periodontium complex. Different strategies mimicking tooth development or physiological reparation have been applied to tooth regeneration studies, where the application of these nerve- or tooth-derived molecules has been proven effective. However, to date, basic studies in this field leave many vacancies to be filled. This literature review summarizes the recent advances in the basic studies on neural responses and regulation during tooth-periodontium development and homeostasis and points out some research gaps to instruct future studies. Deepening our understanding of the underlying mechanisms of tooth development and diseases will provide more clues for tooth regeneration.
Topics: Odontogenesis; Periodontal Ligament; Tooth; Periodontium; Homeostasis
PubMed: 36430624
DOI: 10.3390/ijms232214150