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Journal of Translational Medicine May 2022Sclerostin is the protein product of the SOST gene and is known for its inhibitory effects on bone formation. The monoclonal antibody against sclerostin has been... (Review)
Review
Sclerostin is the protein product of the SOST gene and is known for its inhibitory effects on bone formation. The monoclonal antibody against sclerostin has been approved as a novel treatment method for osteoporosis. Oral health is one of the essential aspects of general human health. Hereditary bone dysplasia syndrome caused by sclerostin deficiency is often accompanied by some dental malformations, inspiring the therapeutic exploration of sclerostin in the oral and dental fields. Recent studies have found that sclerostin is expressed in several functional cell types in oral tissues, and the expression level of sclerostin is altered in pathological conditions. Sclerostin not only exerts similar negative outcomes on the formation of alveolar bone and bone-like tissues, including dentin and cementum, but also participates in the development of oral inflammatory diseases such as periodontitis, pulpitis, and peri-implantitis. This review aims to highlight related research progress of sclerostin in oral cavity, propose necessary further research in this field, and discuss its potential as a therapeutic target for dental indications and regenerative dentistry.
Topics: Bone and Bones; Dentistry; Humans; Inflammation; Osteogenesis; Osteoporosis
PubMed: 35562828
DOI: 10.1186/s12967-022-03417-4 -
Frontiers in Physiology 2019mTORC1 signaling plays an important role in extracellular and intracellular signals, including growth factors, nutrients, energy metabolism, and stress. However, the...
mTORC1 signaling plays an important role in extracellular and intracellular signals, including growth factors, nutrients, energy metabolism, and stress. However, the functional role of mTORC1 in dentinogenesis is unknown. To study the role of Raptor/mTORC1 in dentinogenesis, an Raptor; Osx-Cre (Rap-Osx) mouse, in which Raptor was conditionally deleted in odontoblasts and dental mesenchymal cells, was generated, and postnatal tooth development was compared between Rap-Osx mice and control littermates. Rap-Osx mice presented a phenotype known as dentinogenesis imperfecta and had smaller tooth volume, a thinner dentin layer and a larger pulp chamber. The proliferation and differentiation of odontoblasts/preodontoblasts were attenuated in mutant mice, which was likely responsible for the defects in dentinogenesis. Raptor/mTORC1-pS6K1 signaling was inactivated during tooth development in Rap-Osx mice, whereas it was activated in control mice. These results indicate that Raptor/mTORC1 plays a critical role in dentinogenesis promoting odontoblasts/preodontoblasts proliferation and differentiation. Raptor/mTORC1 might regulate tooth development through the pS6K1 signaling pathway.
PubMed: 30984011
DOI: 10.3389/fphys.2019.00250 -
Genes May 2022Mutations in Dentin Sialophosphoprotein (DSPP) are known to cause, in order of increasing severity, dentin dysplasia type-II (DD-II), dentinogenesis imperfecta type-II...
Mutations in Dentin Sialophosphoprotein (DSPP) are known to cause, in order of increasing severity, dentin dysplasia type-II (DD-II), dentinogenesis imperfecta type-II (DGI-II), and dentinogenesis imperfecta type-III (DGI-III). DSPP mutations fall into two groups: a 5′-group that affects protein targeting and a 3′-group that shifts translation into the −1 reading frame. Using whole-exome sequence (WES) analyses and Single Molecule Real-Time (SMRT) sequencing, we identified disease-causing DSPP mutations in 12 families. Three of the mutations are novel: c.53T>C/p.(Val18Ala); c.3461delG/p.(Ser1154Metfs*160); and c.3700delA/p.(Ser1234Alafs*80). We propose genetic analysis start with WES analysis of proband DNA to identify mutations in COL1A1 and COL1A2 causing dominant forms of osteogenesis imperfecta, 5′-DSPP mutations, and 3′-DSPP frameshifts near the margins of the DSPP repeat region, and SMRT sequencing when the disease-causing mutation is not identified. After reviewing the literature and incorporating new information showing distinct differences in the cell pathology observed between knockin mice with 5′-Dspp or 3′-Dspp mutations, we propose a modified Shields Classification based upon the causative mutation rather than phenotypic severity such that patients identified with 5′-DSPP defects be diagnosed as DGI-III, while those with 3′-DSPP defects be diagnosed as DGI-II.
Topics: Animals; Dentinogenesis Imperfecta; Extracellular Matrix Proteins; Humans; Mice; Mutation; Pedigree; Phosphoproteins; Sialoglycoproteins
PubMed: 35627243
DOI: 10.3390/genes13050858 -
Stem Cells and Development May 2019Tooth development is regulated by sequential and reciprocal epithelium-mesenchymal interactions and their related molecular signaling pathways, such as bone...
Tooth development is regulated by sequential and reciprocal epithelium-mesenchymal interactions and their related molecular signaling pathways, such as bone morphogenetic proteins (BMPs). Among the 14 types of BMPs, BMP9 (also known as growth differentiation factor 2) is one of the most potent BMPs to induce osteogenic differentiation of mesenchymal stem cells. The purpose of this study was to examine potential roles of BMP9 signaling in tooth development. First, we detected the expression pattern of BMP9 in tooth germ during postnatal tooth development, and we found that BMP9 was widely expressed in odontoblasts, ameloblasts, dental pulp cells, and osteoblasts in alveolar bones. Then, we established a -KO mouse model. Gross morphological examination revealed that the tooth cusps of -KO mice were significantly abraded with shorter roots. Micro-computed tomography and three-dimensional reconstruction analysis indicated that the first molars of the -KO mice exhibited a reduced thickness dentin, enlarged pulp canals, and shortened roots, resembling the phenotypes of the common hereditary dental disease dentinogenesis imperfecta. Further, the alveolar bone of the -KO mutants was found to be shorter and had a decreased mineral density and trabecular thickness and bone volume fraction compared with that of the wild-type control. Mechanistically, we demonstrated that both dentin sialophosphoprotein and dentin matrix protein 1 were induced in dental stem cells by BMP9, whereas their expression was reduced when BMP9 was silenced. Further studies are required to determine whether loss of or decreased BMP9 expression is clinically associated with dentinogenesis imperfecta. Collectively, our results strongly suggest that BMP9 may play an important role in regulating dentinogenesis and tooth development. Further research is recommended into the therapeutic uses of BMP9 to regenerate traumatized and diseased tissues and for the bioengineering of replacement teeth.
Topics: Ameloblasts; Animals; Cell Differentiation; Dental Pulp; Dentin; Dentinogenesis Imperfecta; Epithelial-Mesenchymal Transition; Extracellular Matrix Proteins; Gene Expression Regulation; Growth Differentiation Factor 2; Mesenchymal Stem Cells; Mice; Mice, Inbred C57BL; Mice, Knockout; Odontoblasts; Odontogenesis; Osteoblasts; Osteogenesis; Phosphoproteins; Sialoglycoproteins; Tooth; Tooth Germ
PubMed: 30816068
DOI: 10.1089/scd.2018.0230 -
Bioengineering (Basel, Switzerland) Dec 2022The teeth, made up of hard and soft tissues, represent complex functioning structures of the oral cavity, which are frequently affected by processes that cause... (Review)
Review
The teeth, made up of hard and soft tissues, represent complex functioning structures of the oral cavity, which are frequently affected by processes that cause structural damage that can lead to their loss. Currently, replacement therapy such as endodontics or implants, restore structural defects but do not perform any biological function, such as restoring blood and nerve supplies. In the search for alternatives to regenerate the dental pulp, two alternative regenerative endodontic procedures (REP) have been proposed: (I) cell-free REP (based in revascularization and homing induction to remaining dental pulp stem cells (DPSC) and even stem cells from apical papilla (SCAP) and (II) cell-based REP (with exogenous cell transplantation). Regarding the last topic, we show several limitations with these procedures and therefore, we propose a novel regenerative approach in order to revitalize the pulp and thus restore homeostatic functions to the dentin-pulp complex. Due to their multifactorial biological effects, the use of mesenchymal stem cells (MSC)-derived secretome from non-dental sources could be considered as inducers of DPSC and SCAP to completely regenerate the dental pulp. In partial pulp damage, appropriate stimulate DPSC by MSC-derived secretome could contribute to formation and also to restore the vasculature and nerves of the dental pulp.
PubMed: 36671576
DOI: 10.3390/bioengineering10010004 -
Orphanet Journal of Rare Diseases Feb 2023Osteogenesis imperfecta (OI) is a rare, connective tissue disorder characterised by bone fragility, resulting in recurrent fractures and skeletal deformities....
BACKGROUND
Osteogenesis imperfecta (OI) is a rare, connective tissue disorder characterised by bone fragility, resulting in recurrent fractures and skeletal deformities. Extra-skeletal manifestations include dentinogenesis imperfecta, hearing abnormalities and lung disease. These co-morbidities combined with recurrent fractures can exert a significant impact on health-related quality of life (HR-QOL). It is important to assess HR-QOL throughout adulthood because the prevalence of some OI-specific complications increases with age.
METHODS
PubMed, EMBASE and CENTRAL databases were searched on 2nd February 2022 to identify studies reporting quantitative assessments of HR-QOL in adults with OI. The primary endpoint was to determine the impact of an OI diagnosis on adult's HR-QOL. Secondary endpoints were to (i) examine how frequently various HR-QOL assessment tools were used (ii) identify differences in HR-QOL between OI types and (iii) investigate the determinants of HR-QOL in adults with OI. Search results were exported to Endnote where two reviewers independently conducted title/abstract and full-text reviews. Data from accepted studies were extracted into Microsoft Excel. A narrative synthesis was then undertaken.
RESULTS
The review identified 17 studies with a total of 1,648 adults. The Short Form-36 (SF-36) was the most frequently reported HR-QOL assessment tool and was used in nine studies. Physical HR-QOL was reduced in adults with OI. Physical component scores (PCS) or individual physical domains of the SF-36 were lower in eight of nine studies. Mental component scores (MCS) were preserved in all six studies, however individual mental health domains of the SF-36 were reduced in some studies. The prevalence of anxiety/depression was relatively low in adults with OI. Those with type III OI had lower physical and respiratory HR-QOL but preserved mental HR-QOL compared with type I. The prevalence of fatigue and pain was higher in adults with OI compared with reference populations. Age and cardio-pulmonary co-morbidities were associated with lower HR-QOL.
CONCLUSION
OI in adulthood has a wide-ranging negative impact on HR-QOL. Physical and respiratory HR-QOL were lower, while the prevalence of pain and fatigue were higher than in reference populations. Mental HR-QOL was relatively preserved, although some deficits were identified. Age and cardio-pulmonary co-morbidities were associated with lower HR-QOL.
Topics: Adult; Humans; Osteogenesis Imperfecta; Quality of Life; Pain; Fatigue; Prevalence
PubMed: 36814291
DOI: 10.1186/s13023-023-02643-3 -
BMC Oral Health Apr 2023The dentinogenesis differentiation of dental pulp stem cells (DPSCs) is controlled by the spatio-temporal expression of differentiation related genes. RNA...
BACKGROUND
The dentinogenesis differentiation of dental pulp stem cells (DPSCs) is controlled by the spatio-temporal expression of differentiation related genes. RNA N6-methyladenosine (mA) methylation, one of the most abundant internal epigenetic modification in mRNA, influences various events in RNA processing, stem cell pluripotency and differentiation. Methyltransferase like 3 (METTL3), one of the essential regulators, involves in the process of dentin formation and root development, while mechanism of METTL3-mediated RNA mA methylation in DPSC dentinogenesis differentiation is still unclear.
METHODS
Immunofluorescence staining and MeRIP-seq were performed to establish mA modification profile in dentinogenesis differentiation. Lentivirus were used to knockdown or overexpression of METTL3. The dentinogenesis differentiation was analyzed by alkaline phosphatase, alizarin red staining and real time RT-PCR. RNA stability assay was determined by actinomycin D. A direct pulp capping model was established with rat molars to reveal the role of METTL3 in tertiary dentin formation.
RESULTS
Dynamic characteristics of RNA mA methylation in dentinogenesis differentiation were demonstrated by MeRIP-seq. Methyltransferases (METTL3 and METTL14) and demethylases (FTO and ALKBH5) were gradually up-regulated during dentinogenesis process. Methyltransferase METTL3 was selected for further study. Knockdown of METTL3 impaired the DPSCs dentinogenesis differentiation, and overexpression of METTL3 promoted the differentiation. METTL3-mediated mA regulated the mRNA stabiliy of GDF6 and STC1. Furthermore, overexpression of METTL3 promoted tertiary dentin formation in direct pulp capping model.
CONCLUSION
The modification of mA showed dynamic characteristics during DPSCs dentinogenesis differentiation. METTL3-mediated mA regulated in dentinogenesis differentiation through affecting the mRNA stability of GDF6 and STC1. METTL3 overexpression promoted tertiary dentin formation in vitro, suggesting its promising application in vital pulp therapy (VPT).
Topics: Animals; Rats; Cell Differentiation; Dental Pulp; Dentinogenesis; Methyltransferases; RNA; RNA Stability; RNA, Messenger; Stem Cells
PubMed: 37041485
DOI: 10.1186/s12903-023-02836-z -
Journal of Bone and Mineral Research :... Feb 2022Considerable amount of research has been focused on dentin mineralization, odontoblast differentiation, and their application in dental tissue engineering. However, very...
Considerable amount of research has been focused on dentin mineralization, odontoblast differentiation, and their application in dental tissue engineering. However, very little is known about the differential role of functionally and spatially distinct types of dental epithelium during odontoblast development. Here we show morphological and functional differences in dentin located in the crown and roots of mouse molar and analogous parts of continuously growing incisors. Using a reporter (DSPP-cerulean/DMP1-cherry) mouse strain and mice with ectopic enamel (Spry2 ;Spry4 ), we show that the different microstructure of dentin is initiated in the very beginning of dentin matrix production and is maintained throughout the whole duration of dentin growth. This phenomenon is regulated by the different inductive role of the adjacent epithelium. Thus, based on the type of interacting epithelium, we introduce more generalized terms for two distinct types of dentins: cementum versus enamel-facing dentin. In the odontoblasts, which produce enamel-facing dentin, we identified uniquely expressed genes (Dkk1, Wisp1, and Sall1) that were either absent or downregulated in odontoblasts, which form cementum-facing dentin. This suggests the potential role of Wnt signalling on the dentin structure patterning. Finally, we show the distribution of calcium and magnesium composition in the two developmentally different types of dentins by utilizing spatial element composition analysis (LIBS). Therefore, variations in dentin inner structure and element composition are the outcome of different developmental history initiated from the very beginning of tooth development. Taken together, our results elucidate the different effects of dental epithelium, during crown and root formation on adjacent odontoblasts and the possible role of Wnt signalling which together results in formation of dentin of different quality. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Topics: Animals; Cell Differentiation; Dentin; Epithelium; Extracellular Matrix Proteins; Incisor; Mice; Odontoblasts; Odontogenesis
PubMed: 34783080
DOI: 10.1002/jbmr.4471 -
International Journal of Molecular... Jun 2020With increasing life expectancy, demands for dental tissue and whole-tooth regeneration are becoming more significant. Despite great progress in medicine, including... (Review)
Review
With increasing life expectancy, demands for dental tissue and whole-tooth regeneration are becoming more significant. Despite great progress in medicine, including regenerative therapies, the complex structure of dental tissues introduces several challenges to the field of regenerative dentistry. Interdisciplinary efforts from cellular biologists, material scientists, and clinical odontologists are being made to establish strategies and find the solutions for dental tissue regeneration and/or whole-tooth regeneration. In recent years, many significant discoveries were done regarding signaling pathways and factors shaping calcified tissue genesis, including those of tooth. Novel biocompatible scaffolds and polymer-based drug release systems are under development and may soon result in clinically applicable biomaterials with the potential to modulate signaling cascades involved in dental tissue genesis and regeneration. Approaches for whole-tooth regeneration utilizing adult stem cells, induced pluripotent stem cells, or tooth germ cells transplantation are emerging as promising alternatives to overcome existing in vitro tissue generation hurdles. In this interdisciplinary review, most recent advances in cellular signaling guiding dental tissue genesis, novel functionalized scaffolds and drug release material, various odontogenic cell sources, and methods for tooth regeneration are discussed thus providing a multi-faceted, up-to-date, and illustrative overview on the tooth regeneration matter, alongside hints for future directions in the challenging field of regenerative dentistry.
Topics: Animals; Biocompatible Materials; Dental Enamel; Drug Carriers; Humans; Odontogenesis; Regeneration; Signal Transduction; Stem Cells; Tissue Engineering; Tissue Scaffolds; Tooth
PubMed: 32512908
DOI: 10.3390/ijms21114031 -
Journal of Dental Research Jul 2019Dentin sialophosphoprotein (DSPP) is an extracellular matrix protein highly expressed by odontoblasts in teeth. DSPP mutations in humans may cause dentinogenesis...
Dentin sialophosphoprotein (DSPP) is an extracellular matrix protein highly expressed by odontoblasts in teeth. DSPP mutations in humans may cause dentinogenesis imperfecta (DGI), an autosomal dominant dentin disorder. We recently generated a mouse model (named " mice") that expressed a mutant DSPP in which the proline residue at position 19 was replaced by a leucine residue. We found that the and mice at a younger age displayed a tooth phenotype resembling human DGI type III characterized by enlarged dental pulp chambers, while the teeth of older and mice had smaller dental pulp chambers mimicking DGI type II. The teeth of and mice had a narrower pulp chamber roof predentin layer, thinner pulp chamber roof dentin, and thicker pulp chamber floor dentin. In addition, these mice also had increased enamel attrition, accompanied by excessive deposition of peritubular dentin. Immunohistochemistry, in situ hybridization, and real-time polymerase chain reaction analyses showed that the odontoblasts in both and mice had reduced DSPP expression, compared to the wild-type mice. We also observed that the levels of DSPP expression were much higher in the roof-forming odontoblasts than in the floor-forming odontoblasts in the wild-type mice and mutant mice. Moreover, immunohistochemistry showed that while the immunostaining signals of dentin sialoprotein (N-terminal fragment of DSPP) were decreased in the dentin matrix, they were remarkably increased in the odontoblasts of the and mice. Consistently, our in vitro studies showed that the secretion of the mutant DSPP was impaired and accumulated within endoplasmic reticulum. These findings suggest that the dental phenotypes of the mutant mice were associated with the intracellular retention of the mutant DSPP in the odontoblasts of the DSPP-mutant mice.
Topics: Animals; Dentin; Dentinogenesis; Dentinogenesis Imperfecta; Disease Models, Animal; Extracellular Matrix Proteins; Humans; Mice; Odontoblasts; Phosphoproteins; Sialoglycoproteins
PubMed: 31173534
DOI: 10.1177/0022034519854029