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| Canonical Wnt signaling. (A) Inactivated canonical Wnt signaling pathway. (B) Activated canonical Wnt signaling pathway.
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Appropriate tooth root formation and tooth eruption are critical for achieving and maintaining good oral health and quality of life. Tooth eruption is the process through which teeth emerge from their intraosseous position to their functional position in the oral cavity. This temporospatial process occurs simultaneously with tooth root formation th...
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... canonical pathway regulates the function of cells through the intracellular β-catenin levels mediated by the Frizzled (FZD) receptors. In the absence of Wnt ligands, the cytoplasmic β-catenin binds to a protein complex comprised of adenomatous polyposis coli (APC), axin, and glycogen synthase kinase 3 (GSK3), then β-catenin is phosphorylated and targeted for degradation [ Figure 1A; (22)]. In the presence of Wnt ligands, the ligands bind to an FZD receptor and inactivate the β-catenin degradation causing the accumulation of β-catenin that induces the translocation of cytoplasmic β-catenin to the nucleus, then further regulates the transcription of Wnt target genes [Figure 1B; (23)]. ...
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The fibroblast growth factor (FGF) pathway plays an important role in epithelial-mesenchymal interactions during tooth development. Nevertheless, how the ligands, receptors, and antagonists of the FGF pathway are involved in epithelial-mesenchymal interactions remains largely unknown. Miniature pigs exhibit tooth anatomy and replacement patterns li...
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... Dentalanomalies can occur in primary teeth and permanent teeth. The development of the teeth is regulated by molecularand cellular interactions and any disruptions or disturbances during the phases of initiation, morphogenesis and histodifferentiation can lead to the development of dental anomalies [11][12][13][14]. Previous studiesreported that mutations in some gene families such as Msh Homeobox 1 (MSX1) andpaired box 9 (PAX9) may play a role in the development of different developmental dental anomalies [15,16]. ...
Background and objectives: Dental anomalies are significant deviation in the normal size, structure, number, root formation or shape of a tooth. It can affect primary and permanent dentition. The aim of the present study was to determine the prevalence of developmental dental hard tissue anomalies in the permanent dentition of adolescents in two southeastern Nigerian rural communities. Materials and methods: This cross-sectional descriptive study was conducted among school children aged 12-13 years attending two public secondary schools. The schools were located in Nkanu-West and Udi Local Government areas in Enugu state. Oral examination for the presence or absence of developmental dental hard tissue anomalies was performed by a single examiner. Statistical analysis was done using SPSS Version 25. Results: A total of 61 (44.9%) males and 75(55.1%) females participated in the study. The age range of the children was 12 to 13 years with mean age of 12.49 ± 0.50 years. The prevalence of developmental dental hard tissue anomalies was 2.2%. Developmental dental hard tissue anomalies were seen only in females, higher among 13-year-old school children and school children from middle socioeconomic status. Enamel hypoplasia was seen more than peg shaped lateral incisor. There was no statistically significant association with sex (p = 0.25), age (p = 0.61), socioeconomic status (p= 0.25) and developmental dental hard tissue anomalies. Conclusion: The prevalence of developmental dental hard tissue anomalies was low in this study. Developmental dental hard tissue anomalies can affect aesthetics and quality of life. A visit to dental clinic for clinical assessment, preventive interventions and management is recommended. January 2025; Vol. 19(1):002. DOI: https://doi.org/10.55010/imcjms.19.002 *Correspondence: Obehi. O Osadolor, Department of Child Dental Health, University of Nigeria Teaching Hospital, Ituku- ozalla, Enugu State. Nigeria. E-mail: osadolorobehi@yahoo.com; © 2025 The Author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0).
... In vivo study show that loss of β-catenin leads to the arrest of odontogenesis during early tooth development 47 . The conditional ablation of β-catenin in osteoblast and odontoblast causes the malformation of the root dentin and cementum 48 . Amerongen et al. have shown that Wnt5a causes activation of Wnt/ β-catenin signaling in the developing skull 46 . ...
Dentin phosphophoryn (DPP) an extracellular matrix protein activates Wnt signaling in DPSCs (dental pulp stem cells). Wnt/β catenin signaling is essential for tooth development but the role of DPP-mediated Wnt5a signaling in odontogenesis is not well understood. Wnt5a is typically considered as a non-canonical Wnt ligand that elicits intracellular signals through association with a specific cohort of receptors and co-receptors in a cell and context–dependent manner. In this study, DPP facilitated the interaction of Wnt5a with Frizzled 5 and LRP6 to induce nuclear translocation of β-catenin. β-catenin has several nuclear binding partners that promote the activation of Wnt target genes responsible for odontogenic differentiation. Interestingly, steady increase in the expression of Vangl2 receptor suggest planar cell polarity signaling during odontogenic differentiation. In vitro observations were further strengthened by the low expression levels of Wnt5a and β-catenin in the teeth of DSPP KO mice which exhibit impaired odontoblast differentiation and defective dentin mineralization. Together, this study suggests that the DPP-mediated Wnt5a signaling could be exploited as a therapeutic approach for the differentiation of dental pulp stem cells into functional odontoblasts and dentin regeneration.
Supplementary Information
The online version contains supplementary material available at 10.1038/s41598-024-76069-7.
... The Wnt signaling pathway comprises two distinct pathways: The classical β-catenin-dependent pathway and the nonclassical pathway (62). Wnt/β-catenin signaling serves a crucial role in tooth development and eruption, with active expression of Wnt/β-catenin signaling observed in MSCs, including DFCs (63). Wnt signaling is crucial in multiple stages of tooth development and it guides tooth development during fetal formation (64). ...
... Inactivation of Wnt/β-catenin signaling causes tooth root loss or short roots with increased periodontal space. Proper bone resorption and formation are essential for normal tooth eruption, and Wnt/β-catenin signaling is crucial (63,65). In MSCs, classical Wnt signaling promotes the differentiation of DFPCs into osteoblasts rather than chondrocytes and adipocytes (63). ...
... Proper bone resorption and formation are essential for normal tooth eruption, and Wnt/β-catenin signaling is crucial (63,65). In MSCs, classical Wnt signaling promotes the differentiation of DFPCs into osteoblasts rather than chondrocytes and adipocytes (63). Studies have highlighted the dual role of the Wnt signaling pathway in osteoclast formation; β-catenin activation promotes the proliferation of osteoclast progenitor cells at an early stage, after which β-catenin is inactivated to promote osteoclast differentiation (66,67). ...
The dental follicle (DF) plays an indispensable role in tooth eruption by regulating bone remodeling through their influence on osteoblast and osteoclast activity. The process of tooth eruption involves a series of intricate regulatory mechanisms and signaling pathways. Disruption of the parathyroid hormone-related protein (PTHrP) in the PTHrP-PTHrP receptor signaling pathway inhibits osteoclast differentiation by DF cells (DFCs), thus resulting in obstructed tooth eruption. Furthermore, parathyroid hormone receptor-1 mutations are linked to primary tooth eruption failure. Additionally, the Wnt/β-catenin, TGF-β, bone morphogenetic protein and Hedgehog signaling pathways have crucial roles in DFC involvement in tooth eruption. DFC signal loss or alteration inhibits osteoclast differentiation, affects osteoblast and cementoblast differentiation, and suppresses DFC proliferation, thus resulting in failed tooth eruptions. Abnormal tooth eruption is also associated with a range of systemic syndromes and genetic diseases, predominantly resulting from pathogenic gene mutations. Among these conditions, the following disorders arise due to genetic mutations that disrupt DFCs and impede proper tooth eruption: Cleidocranial dysplasia associated with Runt-related gene 2 gene mutations; osteosclerosis caused by CLCN7 gene mutations; mucopolysaccharidosis type VI resulting from arylsulfatase B gene mutations; enamel renal syndrome due to FAM20A gene mutations; and dentin dysplasia caused by mutations in the VPS4B gene. In addition, regional odontodysplasia and multiple calcific hyperplastic DFs are involved in tooth eruption failure; however, they are not related to gene mutations. The specific mechanism for this effect requires further investigation. To the best of our knowledge, previous reviews have not comprehensively summarized the syndromes associated with DF abnormalities manifesting as abnormal tooth eruption. Therefore, the present review aims to consolidate the current knowledge on DFC signaling pathways implicated in abnormal tooth eruption, and their association with disorders of tooth eruption in genetic diseases and syndromes, thereby providing a valuable reference for future related research.
... Nicha Tokavani ch et al. [51] Review Article Wnt signaling and its effect on postnatal tooth development. ...
Dentin pulp has a complex function as a major unit in maintaining the vitality of teeth. In this sense, the Wnt/β-Catenin pathway has a vital part in tooth development, maintenance, repair, and regeneration by controlling physiological activities such as growth, differentiation, and migration. This pathway consists of a network of proteins, such as Wnt signaling molecules, which interact with receptors of targeted cells and play a role in development and adult tissue homeostasis. The Wnt signals are specific spatiotemporally, suggesting its intricate mechanism in development, regulation, repair, and regeneration by the formation of tertiary dentin. This review provides an overview of the recent advances in the Wnt/β-Catenin signaling pathway in dentin and pulp regen-eration, how different proteins, molecules, and ligands influence this pathway, either upregulating or silencing it, and how it may be used in the future for clinical dentistry, in vital pulp therapy as an effective treatment for dental caries, as an alternative approach for root canal therapy, and to provide a path for therapeutic and regenerative dentistry.
... Disturbing WNT signaling in mesenchymal cells during tooth root development causes shortened roots with proliferation and differentiation defects. [30][31][32][33] Taken together, these findings demonstrate that the level of WNT signaling must be tightly controlled for tooth root development to proceed normally. We further established the role of the FGF-WNT signaling cascade in establishing the correct tooth root pattern by modulating the fate commitment of progenitors. ...
Stem/progenitor cells differentiate into different cell lineages during organ development and morphogenesis. Signaling pathway networks and mechanotransduction are important factors to guide the lineage commitment of stem/progenitor cells during craniofacial tissue morphogenesis. Here, we used tooth root development as a model to explore the roles of FGF signaling and mechanotransduction as well as their interaction in regulating the progenitor cell fate decision. We show that Fgfr1 is expressed in the mesenchymal progenitor cells and their progeny during tooth root development. Loss of Fgfr1 in Gli1⁺ progenitors leads to hyperproliferation and differentiation, which causes narrowed periodontal ligament (PDL) space with abnormal cementum/bone formation leading to ankylosis. We further show that aberrant activation of WNT signaling and mechanosensitive channel Piezo2 occurs after loss of FGF signaling in Gli1-CreER;Fgfr1fl/fl mice. Overexpression of Piezo2 leads to increased osteoblastic differentiation and decreased Piezo2 leads to downregulation of WNT signaling. Mechanistically, an FGF/PIEZO2/WNT signaling cascade plays a crucial role in modulating the fate of progenitors during root morphogenesis. Downregulation of WNT signaling rescues tooth ankylosis in Fgfr1 mutant mice. Collectively, our findings uncover the mechanism by which FGF signaling regulates the fate decisions of stem/progenitor cells, and the interactions among signaling pathways and mechanotransduction during tooth root development, providing insights for future tooth root regeneration.
... During tooth development, tooth number, size, and position are regulated by the collaboration of WNT, SHH, FGF, and BMP signaling [1,2]. Normal root morphogenesis requires optimal levels of WNT/β-catenin and SHH signaling [2]. ...
... During tooth development, tooth number, size, and position are regulated by the collaboration of WNT, SHH, FGF, and BMP signaling [1,2]. Normal root morphogenesis requires optimal levels of WNT/β-catenin and SHH signaling [2]. SHH is primarily found in the dental epithelium throughout tooth development, starting from initiation and continuing through root formation stages. ...
... Several stages of tooth development require optimal WNT/β-catenin signaling [2]. Downregulation of WNT/β-catenin signaling in the dental epithelium is implicated in tooth agenesis or microdontia, whereas overactivation of WNT/β-catenin signaling in the dental epithelium is implicated in the formation of supernumerary teeth [1,[6][7][8]. ...
KCTD1 plays crucial roles in regulating both the SHH and WNT/β-catenin signaling pathways, which are essential for tooth development. The objective of this study was to investigate if genetic variants in KCTD1 might also be associated with isolated dental anomalies. We clinically and radiographically investigated 362 patients affected with isolated dental anomalies. Whole exome sequencing identified two unrelated families with rare (p.Arg241Gln) or novel (p.Pro243Ser) variants in KCTD1. The variants segregated with the dental anomalies in all nine patients from the two families. Clinical findings of the patients included taurodontism, unseparated roots, long roots, tooth agenesis, a supernumerary tooth, torus palatinus, and torus mandibularis. The role of Kctd1 in root development is supported by our immunohistochemical study showing high expression of Kctd1 in Hertwig epithelial root sheath. The KCTD1 variants in our patients are the first variants found to be located in the C-terminal domain, which might disrupt protein–protein interactions and/or SUMOylation and subsequently result in aberrant WNT-SHH-BMP signaling and isolated dental anomalies. Functional studies on the p.Arg241Gln variant are consistent with an impact on β-catenin levels and canonical WNT signaling. This is the first report of the association of KCTD1 variants and isolated dental anomalies.
... A radiologic sign of cherubism is root resorption (e.g., on six-year molars) [2]. Although the distal root was formed, it is resorbed in contact with osteoprotegerin = OPG [54] via RANKL = receptor activator of NF-κB ligand (possibly involving MSX1) due to the lack of WNT/ß-catenin signaling. This finding was also described from a radiological perspective (MRI = magnetic resonance imaging) in the same patient, as shown in Figure 2 One clinical sign that we have included here is the integrity of the articular process. ...
Cherubism is nowadays classified as an autoimmune disease and was first described in 1933. Although suspected at that time to be the result of defective tooth development, it was primarily classified as a bone disease caused by a mutation in the SH3BP2 gene. Despite a knock-in mouse model, phenotypic signs in the jaw area were not reproducible in this model. The features of classical cherubism can be attributed to a disturbed formation of the dental placode of the second molar. Since 2019, it has become clear that inhibition of the WNT pathway leads to the accumulation of SH3BP2 via tankyrase inhibition. As the dental placode is triggered via WNT (in epithelia) and MSX1 (in mesenchyme), aplasia of the second and third molars occurs due to a block in the WNT pathway. The mesenchymal part, which occurs prior to the body plan regulation of the WNT/MSX1 pathway, remains unaffected and provides the substrate for the giant cell granuloma. Considering macrophage polarization and the role of the extracellular matrix in general, cherubism is situated in the field of tension between autoimmune diseases and cancer. In this sense, we see the cause of cherubism in a WNT-related dysregulation, which can be proven postnatally in the neural crest-related tooth development of the replacement tooth ridge, both genotypically and phenotypically.
... The Wnt signaling pathway [13,14] as well as its inhibition [15] during various stages of odontogenesis have been shown to dysregulate proliferation, differentiation, and epithelial-mesenchymal interaction in tooth root formation and early development of the teeth [12,16,17]. ...
Background and Objectives: Periodontitis is marked by the destruction of alveolar bone. Sclerostin (SOST) and dickkopf-1 (DKK-1) act as inhibitors of the Wingless-type (Wnt) signaling pathway, a key regulator of bone metabolism. Recent studies have suggested that statins play a role in bone resorption and formation by influencing Wnt signaling. The aim of this study was to determine the levels of SOST and DKK-1 in periodontal patients with and without peroral statins treatment in their therapy. Materials and Methods: A total of 79 patients with diagnosed periodontitis were divided into two groups: 39 patients on statin therapy (SP group) and 40 patients without statin therapy as a control group (P group). The periodontal clinical examination probing (pocket) depth (PD) and gingival recession (GR) were measured, and approximal plaque was detected, while vertical and horizontal bone resorption was measured using a panoramic radiograph image. Clinical attachment loss (CAL) values were calculated using PD and GR values. Gingival crevicular fluid (GCF) was collected and used for measuring SOST and DKK-1 levels. A questionnaire was used to assess lifestyle habits and statin intake. Patients’ medical records were used to obtain biochemical parameters. Results: There was no significant difference in sclerostin concentration between the SP and P group. DKK-1 values were significantly higher in the SP group compared to the control group (p = 0.04). Also, PD (p = 0.001) and GR (p = 0.03) were significantly higher in the SP group. The level of DKK-1 had a positive relationship with the PD, the greater the PD, the higher the level of DKK-1 (Rho = 0.350), while there was no significant association with other parameters. Conclusions: Peroral statins in periodontal patients are associated with GCF levels of DKK-1 but not with sclerostin levels.
... The canonical Wnt signaling plays an important role in tooth root development. 31,32 Wnt10a, a ligand of the canonical Wnt pathway, presents intensive expression in odontoblast cells adjacent to dental epithelium. 20 A recent study proved that Wnt10a induced pupal mesenchyme progenitors residing in furcation region to differentiate into odontoblasts and form a horizontal dentin bridge, whereas inhibition of Wnt10a expression disrupted dentin bridge formation and resulted in taurodontism. ...
Human with bi-allelic WNT10A mutations and epithelial Wnt10a knockout mice present enlarged pulp chamber and apical displacement of the root furcation of multi-rooted teeth, known as taurodontism; thus, indicating the critical role of Wnt10a in tooth root morphogenesis. However, the endogenous mechanism by which epithelial Wnt10a regulates Hertwig’s epithelial root sheath (HERS) cellular behaviors and contributes to root furcation patterning remains unclear. In this study, we found that HERS in the presumptive root furcating region failed to elongate at an appropriate horizontal level in K14-Cre;Wnt10a fl/fl mice from post-natal day 0.5 (PN0.5) to PN4.5. EdU assays and immunofluorescent staining of cyclin D1 revealed significantly decreased proliferation activity of inner enamel epithelial (IEE) cells of HERS in K14-Cre;Wnt10a fl/fl mice at PN2.5 and PN3.5. Immunofluorescent staining of E-Cadherin and acetyl-α-Tubulin demonstrated that the IEE cells of HERS tended to divide perpendicularly to the horizontal plane, which impaired the horizontal extension of HERS in the presumptive root furcating region of K14-Cre;Wnt10a fl/fl mice. RNA-seq and immunofluorescence showed that the expressions of Jag1 and Notch2 were downregulated in IEE cells of HERS in K14-Cre;Wnt10a fl/fl mice. Furthermore, after activation of Notch signaling in K14-Cre;Wnt10a fl/fl molars by Notch2 adenovirus and kidney capsule grafts, the root furcation defect was partially rescued. Taken together, our study demonstrates that an epithelial Wnt10a-Notch signaling axis is crucial for modulating HERS cell proper proliferation and horizontal-oriented division during tooth root furcation morphogenesis.
... In this area, activation of SHH pathway is crucial for cell proliferation and the perturbation of the signal results in the short root phenotype Nakatomi et al., 2006). Similarly, expression of WNT genes and Axin2, a target gene of Wnt/β-catenin signalling, is found in the HERS and dental mesenchyme, and WNT pathway is indispensable for odontoblast differentiation during root formation (Lohi et al., 2010;Tokavanich et al., 2021;Yamashiro et al., 2007).Although particular factors have attracted more attention, FGF signalling has been left relatively unexplored in tooth root development, albeit its pivotal roles in hard tissue formation (Ornitz & Marie, 2015;Su et al., 2014). Few FGF ligands and their receptors have been analysed in crown-to-root transition stage during tooth development, and those in progressive stages of root development as well as the interactions with other pathways remain largely obscured (Baba et al., 2015;Balic & Thesleff, 2015;Yokohama-Tamaki et al., 2006). ...
Fibroblast growth factor (FGF) signalling plays a crucial role in the morphogenesis of multiple tissues including teeth. While the role of the signal has been studied in tooth crown development, little is known about root development. Of several FGF ligands involved in hard tissue formation, we suggest that FGF18 regulates the development of murine tooth roots. We implanted FGF18‐soaked heparin beads into the lower first molar tooth buds at postnatal day 6 (P6), followed by transplantation under the kidney capsule. After 3 weeks, FGF18 significantly facilitated root elongation and periodontal tissue formation compared to the control. In situ hybridisation showed that Fgf18 transcripts were initially localised in the dental pulp along Hertwig's epithelial root sheath at P6 and P10 and subsequently in the dental follicle cells at P14. Fgf receptors were expressed in various dental tissues during these stages. In vitro analysis using the dental pulp stem cells revealed that FGF18 inhibited cell proliferation and decreased expression levels of osteogenic markers, Runx2 , Alpl and Sp7 . Consistently, after 1 week of kidney capsule transplantation, FGF18 application did not induce the expression of Sp7 and Bsp , but upregulated Periostin in the apical region of dental mesenchyme in the grafted molar. These findings suggest that FGF18 facilitates molar root development by regulating the calcification of periodontal tissues.
