scholarly journals Anti–USAG-1 therapy for tooth regeneration through enhanced BMP signaling

2021 ◽  
Vol 7 (7) ◽  
pp. eabf1798
Author(s):  
A. Murashima-Suginami ◽  
H. Kiso ◽  
Y. Tokita ◽  
E. Mihara ◽  
Y. Nambu ◽  
...  
Keyword(s):  
Tooth Development ◽  
Bmp Signaling ◽  
Tooth Agenesis ◽  
Tooth Regeneration ◽  
Missing Teeth ◽  
Morphogenetic Protein ◽  
Genetic Abnormalities ◽  
Direct Binding ◽  
Tooth Germs ◽  
Lipoprotein Receptor Related Protein

Uterine sensitization–associated gene-1 (USAG-1) deficiency leads to enhanced bone morphogenetic protein (BMP) signaling, leading to supernumerary teeth formation. Furthermore, antibodies interfering with binding of USAG-1 to BMP, but not lipoprotein receptor–related protein 5/6 (LRP5/6), accelerate tooth development. Since USAG-1 inhibits Wnt and BMP signals, the essential factors for tooth development, via direct binding to BMP and Wnt coreceptor LRP5/6, we hypothesized that USAG-1 plays key regulatory roles in suppressing tooth development. However, the involvement of USAG-1 in various types of congenital tooth agenesis remains unknown. Here, we show that blocking USAG-1 function through USAG-1 knockout or anti–USAG-1 antibody administration relieves congenital tooth agenesis caused by various genetic abnormalities in mice. Our results demonstrate that USAG-1 controls the number of teeth by inhibiting development of potential tooth germs in wild-type or mutant mice missing teeth. Anti–USAG-1 antibody administration is, therefore, a promising approach for tooth regeneration therapy.

Bone Morphogenetic Protein 2 Coordinates Early Tooth Mineralization

2018 ◽  
Vol 97 (7) ◽  
pp. 835-843 ◽  
Author(s):  
Z. Malik ◽  
M. Alexiou ◽  
B. Hallgrimsson ◽  
A.N. Economides ◽  
H.U. Luder ◽  
...  
Keyword(s):  
Tooth Development ◽  
Bmp Signaling ◽  
Conditional Knockout ◽  
Bone Morphogenetic Protein 2 ◽  
Micro Computed Tomography ◽  
Tooth Mineralization ◽  
Morphogenetic Protein ◽  
Dental Hard Tissues ◽  
Dentin Sialoprotein ◽  
Tooth Germs

Formation of highly organized dental hard tissues is a complex process involving sequential and ordered deposition of an extracellular scaffold, followed by its mineralization. Odontoblast and ameloblast differentiation involves reciprocal and sequential epithelial-mesenchymal interactions. Similar to early tooth development, various Bmps are expressed during this process, although their functions have not been explored in detail. Here, we investigated the role of odontoblast-derived Bmp2 for tooth mineralization using Bmp2 conditional knockout mice. In developing molars, Bmp2LacZ reporter mice revealed restricted expression of Bmp2 in early polarized and functional odontoblasts while it was not expressed in mature odontoblasts. Loss of Bmp2 in neural crest cells, which includes all dental mesenchyme, caused a delay in dentin and enamel deposition. Immunohistochemistry for nestin and dentin sialoprotein (Dsp) revealed polarization defects in odontoblasts, indicative of a role for Bmp2 in odontoblast organization. Surprisingly, pSmad1/5/8, an indicator of Bmp signaling, was predominantly reduced in ameloblasts, with reduced expression of amelogenin ( Amlx), ameloblastin ( Ambn), and matrix metalloproteinase ( Mmp20). Quantitative real-time polymerase chain reaction (RT-qPCR) analysis and immunohistochemistry showed that loss of Bmp2 resulted in increased expression of the Wnt antagonists dickkopf 1 ( Dkk1) in the epithelium and sclerostin ( Sost) in mesenchyme and epithelium. Odontoblasts showed reduced Wnt signaling, which is important for odontoblast differentiation, and a strong reduction in dentin sialophosphoprotein ( Dspp) but not collagen 1 a1 ( Col1a1) expression. Mature Bmp2-deficient teeth, which were obtained by transplanting tooth germs from Bmp2-deficient embryos under a kidney capsule, showed a dentinogenesis imperfecta type II–like appearance. Micro–computed tomography and scanning electron microscopy revealed reduced dentin and enamel thickness, indistinguishable primary and secondary dentin, and deposition of ectopic osteodentin. This establishes that Bmp2 provides an early temporal, nonredundant signal for directed and organized tooth mineralization.

Stage- and tissue-specific effect of cyclophosphamide during tooth development

2019 ◽  
Vol 41 (5) ◽  
pp. 519-530
Author(s):  
Kohei Nakatsugawa ◽  
Hiroshi Kurosaka ◽  
Toshihiro Inubushi ◽  
Gozo Aoyama ◽  
Yukako Isogai ◽  
...  
Keyword(s):  
Root Formation ◽  
Histological Analysis ◽  
Developmental Stages ◽  
Tooth Development ◽  
Specific Effect ◽  
Tooth Agenesis ◽  
Histological Observation ◽  
Micro Computed Tomography ◽  
Tooth Germs ◽  
Morphological Phenotype

Summary Objective The aim of this study was to investigate the toxic effect of cyclophosphamide (CPA) in the development of rodent molars. Methods CPA was administered intraperitoneally in postnatal mice between Day 1 and Day 10, and the morphological phenotype was evaluated at Day 26 using micro-computed tomography and histological analysis, including cell proliferation and cell death analyses. Results M3 molars of the mice who received 100 mg/kg CPA treatment at Day 6 or M2 molars who received treatment at Day 1 resulted in tooth agenesis or marked hypoplasia. Histological observation demonstrated that CPA treatment at Day 6 resulted in shrinkage of the M3 tooth germs, with a significant reduction in the proliferation of apoptotic cells. Conversely, CPA exposure at Day 2, which occurs at around the bud stage of M3, resulted in crown and root hypoplasia, with reduced numbers of cusp and root. In addition, CPA exposure at Day 10, which is the late bell stage of M3, induced root shortening; however, it did not affect crown morphogenesis. Limitations The timing of CPA administration is limited to after birth. Therefore, its effect during the early stages of M1 and M2 could not be investigated. Conclusion Defective phenotypes were evident in both crown and roots due to the effect of CPA. Interestingly, the severity of the phenotypes was associated with the developmental stages of the tooth germs at the time of CPA administration. The cap/early bell stage is the most susceptive timing for tooth agenesis, whereas the late bell stage is predominantly affected in terms of root formation by CPA administration.

scholarly journals Noggin Is Required for Early Development of Murine Upper Incisors

2012 ◽  
Vol 91 (4) ◽  
pp. 394-400 ◽  
Author(s):  
X. Hu ◽  
Y. Wang ◽  
F. He ◽  
L. Li ◽  
Y. Zheng ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tooth Development ◽  
Multiple Organ ◽  
Bmp Signaling ◽  
Lower Incisor ◽  
Molar Teeth ◽  
Bmp Antagonists ◽  
Initiation Stage ◽  
Tooth Germs ◽  
Bmp Antagonist

BMP signaling plays crucial roles in the development of many organs, including the tooth. Equally important is BMP signaling homeostasis, as demonstrated by multiple organ defects in mice lacking the extracellular BMP antagonist Noggin. Here, we show that Noggin is initially expressed in the maxillary mesenchyme adjunct to the upper incisor at the initiation stage, and then in the developing teeth, including incisors and molars, from the bud stage. Noggin mutants develop normal molars and mandibular incisors, but form a single, medially located upper incisor that is arrested at the late bud stage. Histological and molecular marker analyses demonstrated that two distinct upper incisor placodes initiate independently at E11.5, but begin to fuse at E12.5, coupling with elevated cell proliferation rates in the developing tooth germs. We further found that Chordin and Gremlin, two other BMP antagonists, are co-expressed with Noggin in the developing lower incisor and molar teeth. These observations indicate the importance of BMP signaling homeostasis, and suggest a functional redundancy between BMP antagonists during tooth development.

scholarly journals Prevalence of Hypodontia in the Permanent Dentition of Macedonian Population

2014 ◽  
Vol 18 (2) ◽  
pp. 93-98
Author(s):  
Darko Pop Acev ◽  
Julijana Gjorgova
Keyword(s):  
Tooth Development ◽  
Cross Sectional Study ◽  
Tooth Agenesis ◽  
Missing Teeth ◽  
Cross Sectional ◽  
Congenitally Missing Teeth ◽  
Albanian Population ◽  
Congenitally Missing ◽  
Missing Tooth ◽  
Functional Deficiency

SUMMARYHypodontia or tooth agenesis is a condition at which the patient is missing one or more teeth due to a failure of those teeth to develop. This is not only an aesthetic, but also a functional deficiency. The incidence of congenitally missing teeth depends on etiological factors that affect tooth development, as well as which dentition is concerned, sex or race and geographic distribution. The tooth agenesis is mostly seen in teeth that are formed last in a given class (lateral incisors, second premolars and third molars). The aim of this study was to calculate the prevalence of congenitally missing teeth in population of FYROM and, through a review of the literature, to compare these results to other populations in the world.For this purpose a retrospective, transversal and cross-sectional study was made, where dental history and anamnesis of 8160 patients (3671 males and 4489 females) were examined, as well as their panoramic radiographs. The patients were 8-18 years old. The data was statistically analyzed with programme Statistica 7.0. The prevalence of hypodontia population of FYROM was 7.52%. Most commonly congenitally missing tooth in patients with hypodontia was mandibular second premolar (35.5% left and 34.53% right). Tooth agenesis predominated in females and in ethnic Albanian population, without significance.

scholarly journals Evaluation and Immunolocalization of BMP4 and FGF8 in Odontogenic Cyst and Tumors

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Neeti Swarup ◽  
Meghanand T. Nayak ◽  
Zoya Chowdhary ◽  
Monica Mehendiratta ◽  
Shikha Khatana ◽  
...  
Keyword(s):  
Growth Factors ◽  
Tooth Development ◽  
Research Work ◽  
Odontogenic Cyst ◽  
Odontogenic Cysts ◽  
Fibroblast Growth Factor 8 ◽  
Nuclear Expression ◽  
Morphogenetic Protein ◽  
Ameloblastic Fibroma ◽  
Tooth Germs

Growth factors like bone morphogenetic protein 4 (BMP4) and fibroblast growth factor 8 (FGF8) play a major role in organogenesis and specifically in odontogenesis. They are also believed to have a role in oncogenesis. Thus, any discrepancies in their standard behavior and activity would lead to serious abnormalities including odontogenic cyst and tumors. The present research work investigated the expression of BMP4 and FGF8 in odontogenic tumors (OT) and cyst as well as developing tooth germs to elucidate their roles. Dental organs of various odontogenic stages and 30 OTs including solid multicystic ameloblastomas (SMA, 10 cases), ameloblastic fibroma (AF, 10 cases), odontogenic myxoma (OM, 10 cases), and odontogenic cysts: odontogenic keratocyst (OKC, 10 cases) were evaluated in both epithelial and mesenchymal components for the expression of BMP4 and FGF8 using immunohistochemistry. The epithelial nuclear expression of BMP4 was highest in OKC (9 cases) while FGF8 was highest in SMA (10 cases). The mesenchymal nuclear expression of both BMP4 (8 cases) (p=0.001) and FGF8 (9 cases) (p=0.045) were significantly high in OMs among all OTs. Both growth factors were actively expressed in different stages of tooth development. The expression of BMP4 and FGF8 corelates well with the proliferative component of the pathologies, indicating a possible role in the pathogenesis and progression.

scholarly journals Synergistic Mutations of LRP6 and WNT10A in Familial Tooth Agenesis

2021 ◽  
Vol 11 (11) ◽  
pp. 1217
Author(s):  
Kuan-Yu Chu ◽  
Yin-Lin Wang ◽  
Yu-Ren Chou ◽  
Jung-Tsu Chen ◽  
Yi-Ping Wang ◽  
...  
Keyword(s):  
Tooth Development ◽  
Wide Spectrum ◽  
Genetic Diagnosis ◽  
Dose Dependence ◽  
Tooth Agenesis ◽  
Missense Mutations ◽  
Craniofacial Anomalies ◽  
Loss Of Function ◽  
Missing Teeth ◽  
Digenic Inheritance

Familial tooth agenesis (FTA), distinguished by developmental failure of selected teeth, is one of the most prevalent craniofacial anomalies in humans. Mutations in genes involved in WNT/β-catenin signaling, including AXIN2 WNT10A, WNT10B, LRP6, and KREMEN1, are known to cause FTA. However, mutational interactions among these genes have not been fully explored. In this study, we characterized four FTA kindreds with LRP6 pathogenic mutations: p.(Gln1252*), p.(Met168Arg), p.(Ala754Pro), and p.(Asn1075Ser). The three missense mutations were predicted to cause structural destabilization of the LRP6 protein. Two probands carrying both an LRP6 mutant allele and a WNT10A variant exhibited more severe phenotypes, suggesting mutational synergism or digenic inheritance. Biallelic LRP6 mutations in a patient with many missing teeth further supported the dose-dependence of LRP6-associated FTA. Analysis of 21 FTA cases with 15 different LRP6 loss-of-function mutations revealed high heterogeneity of disease severity and a distinctive pattern of missing teeth, with maxillary canines being frequently affected. We hypothesized that various combinations of sequence variants in WNT-related genes can modulate WNT signaling activities during tooth development and cause a wide spectrum of tooth agenesis severity, which highlights the importance of exome/genome analysis for the genetic diagnosis of FTA in this era of precision medicine.

scholarly journals Failure of Tooth Development: Prevalence, Genetic Causes and Clinical Features

2021 ◽  
Author(s):  
Emilia Severin ◽  
George Gabriel Moldoveanu ◽  
Andreea Moldoveanu
Keyword(s):  
Tooth Development ◽  
Gene Mutations ◽  
Dental Arch ◽  
Tooth Agenesis ◽  
Missing Teeth ◽  
Related Quality ◽  
Wide Variability ◽  
Health Related ◽  
Clinical Consequences ◽  
Tooth Number

In dental practice may be encountered a wide variability in the clinical dental phenotype of tooth number. Failure of tooth development at the bud stage causes tooth agenesis and reduction in tooth number in the dental arch which involves various complications. Tooth agenesis is one of the most common developmental anomalies of human permanent dentition and tends to run in families, may aggregate within families, suggesting a genetic cause. Tooth agenesis can occur in association with a variety of craniofacial syndromes, but it is also found as an isolated trait (familial or sporadic). Other tooth anomalies, such as tooth shape and size, delayed eruption of teeth, malposition, short roots or taurodontism, have been noted in association with non-syndromic tooth agenesis as well. Both the deciduous and permanent dentitions may be affected by missing teeth. Variations in the number of missing teeth can be determined by a mutation in one gene, by mutations in multiple genes, induced by local or systemically acting environmental factor, caused by a combination of gene mutations and environmental factors acting together, or by damage to chromosomes. As the number of missing teeth increases, so does the severity of clinical consequences and the impact on oral health–related quality of life.

A Rare Case of Congenital Missing Mandibular Second Molar: Report and Review of Literature

2020 ◽  
Author(s):  
Deepashri H Kambalimath
Keyword(s):  
Tooth Development ◽  
Rare Condition ◽  
Review Of Literature ◽  
Indian Literature ◽  
Missing Teeth ◽  
Second Molar ◽  
The World ◽  
Mandibular Second Molar ◽  
Sporadic Cases ◽  
Genetic And Environmental Factors

Congenital missing permanent second molar is an extremely rare condition. Non syndromic mandibular second molar agenesis associated with other anomalies has occasionally been reported in literature, but isolated sporadic cases are rarely observed. Number of interactions between genetic and environmental factors during the process of tooth development might be the causative etiology for agenesis. This report presents an isolated case of hypodontia with absence of bilateral mandibular second molar agenesis in a healthy 18 year old female patient is presented and literature review on prevalence of most missing teeth with incidence of missing second molar in various regions of the world and in various regions of Indian continent is presented. No such case has been reported in Indian literature so far.

scholarly journals GDF11 promotes osteogenesis as opposed to MSTN, and follistatin, a MSTN/GDF11 inhibitor, increases muscle mass but weakens bone

2020 ◽  
Vol 117 (9) ◽  
pp. 4910-4920 ◽  
Author(s):  
Joonho Suh ◽  
Na-Kyung Kim ◽  
Seung-Hoon Lee ◽  
Je-Hyun Eom ◽  
Youngkyun Lee ◽  
...  
Keyword(s):  
Bone Mass ◽  
Muscle Mass ◽  
Transforming Growth Factor ◽  
Bone Fractures ◽  
Muscle Growth ◽  
Transforming Growth Factor Β ◽  
Biochemical Properties ◽  
Bmp Signaling ◽  
Morphogenetic Protein ◽  
Perinatal Lethality

Growth and differentiation factor 11 (GDF11) and myostatin (MSTN) are closely related transforming growth factor β (TGF-β) family members, but their biological functions are quite distinct. While MSTN has been widely shown to inhibit muscle growth, GDF11 regulates skeletal patterning and organ development during embryogenesis. Postnatal functions of GDF11, however, remain less clear and controversial. Due to the perinatal lethality ofGdf11null mice, previous studies used recombinant GDF11 protein to prove its postnatal function. However, recombinant GDF11 and MSTN proteins share nearly identical biochemical properties, and most GDF11-binding molecules have also been shown to bind MSTN, generating the possibility that the effects mediated by recombinant GDF11 protein actually reproduce the endogenous functions of MSTN. To clarify the endogenous functions of GDF11, here, we focus on genetic studies and show thatGdf11null mice, despite significantly down-regulatingMstnexpression, exhibit reduced bone mass through impaired osteoblast (OB) and chondrocyte (CH) maturations and increased osteoclastogenesis, while the opposite is observed inMstnnull mice that display enhanced bone mass. Mechanistically,Mstndeletion up-regulatesGdf11expression, which activates bone morphogenetic protein (BMP) signaling pathway to enhance osteogenesis. Also, mice overexpressing follistatin (FST), a MSTN/GDF11 inhibitor, exhibit increased muscle mass accompanied by bone fractures, unlikeMstnnull mice that display increased muscle mass without fractures, indicating that inhibition of GDF11 impairs bone strength. Together, our findings suggest that GDF11 promotes osteogenesis in contrast to MSTN, and these opposing roles of GDF11 and MSTN must be considered to avoid the detrimental effect of GDF11 inhibition when developing MSTN/GDF11 inhibitors for therapeutic purposes.

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