Timing of appearance of the third dentition (Takahahsi et al., 2013, copy right, In Tech)
1. Introduction
The tooth is a complex organ that consists of enamel, dentin, cementum, and pulp. Missing teeth is frequently occurring problem in aging populations. To treat these defects, the current approach involves prostheses, autotransplantation, and dental implants. The exploration of new strategies for tooth replacement has become a hot topic. Using the foundations of experimental embryology, developmental and molecular biology, tooth regeneration is becoming realistic possibility. Several different methods have been proposed to achieve biological tooth replacement. These include scaffold-based tooth regeneration, cell pellet engineering, stimulation of the formation of a third dentition, and gene-manipulated tooth regeneration. The idea that a third dentition might be locally induced to replace missing teeth is an attractive concept (Young et al., 2005; Edward & Mason, 2006; Takahashi et al., 2008, 2013). This approach is generally presented in terms of adding molecules to induce
2. The third dentition
It has been suggested that, in humans, a “third dentition” with one or more supernumerary teeth can occur in addition to the permanent dentition, and supernumerary teeth are sometimes thought to represent a partial post-permanent dentition (Ooe, 1969). The deciduous teeth are, ontogenetically, the first generation of teeth. The permanent teeth (except molar) belong to the second dentition. The term “third dentition” refers to the opinion that one more set of teeth can occur in addition to the permanent teeth (Figure 1). Human teeth are diphyodont excepting the permanent molars. The normal mouse dentition is monophyodont and composed of one incisor and three molars in each quadrant. The number of teeth is usually strictly determined. It was initially reported that there is an anlagen of the third dentition in some mammals (Leche, 1893). The presence of an epithelial anlagen of the third dentition was also noticed in humans (Ooe, 1969). The teeth and anlagen that appear in third dentition in serial sections of infant jaws and some fetuses have been analysed. The epithelium which is considered as the anlagen of the third dentition develops lingual to all permanent tooth germs (Ooe, 1969). Furthermore, when it appears, the predecessor (permanent tooth germ) is in the bell-shaped stage (Ooe, 1969). The timing of appearance of the third dentition seems to be after birth (Table 1). This means that we have a chance to access the formation of the third dentition in the mouth.
Detailed histological analysis of the tooth replacement in these models indicates that the successional teeth are initiated from the dental lamina epithelium, which grows from the lingual side of the deciduous tooth enamel organ, and it later elongates and buds into the jaw mesenchyme, forming successional teeth. Jarvien et al. showed that, in the ferret,
3. Human syndromes associated with supernumerary teeth
Supernumerary teeth can be associated with a syndrome or they can be found in non-syndromic patients. Only 1% of non-syndromic cases have multiple supernumerary teeth, which occur most frequently in the mandibular premolar area, followed by the molar and anterior regions, respectively (Yusof, 1990; Yague-Garcia et al., 2009). Genetic mutations have been associated with the presence or absence of individual types of teeth.
Supernumerary teeth are associated with 8 syndromes and developmental abnormalities in which the resposible genes already have been isolated (Takahashi et al., 2013). The percentage occurrence in CCD is 22% in the maxillary incisor region and 5% in the molar region (Shafer, 1983). CCD is a dominantly inherited skeletal dysplasia caused by mutations in
Familial adenomatous polyposis (FAP), also named adenomatous polyposis of the colon (APC), is an autosomal dominant hereditary disorder characterized by the development of many precancerous colorectal adenomatous polyps. In addition to colorectal neoplasm, individuals can develop variable extracolonic lesions, including upper gastrointestinal polyposis, osteomas and dental anomalies (Wijn et al., 2007). Dental abnormalities include impacted teeth, congenital absence of one or more teeth, supernumerary teeth and odontomas (Wijn et al., 2007). Gardner syndrome is a variant of FAP characterized by multiple adenomas of the colon and rectum typical of FAP together with osteomas and soft tissue tumors (Chimenos-Kustner et al., 2005). Supernumerary teeth and osteomas were originally described as a part of Gardner syndrome, but they can also occur in FAP patients with or without other extracolonic lesions (Chimenos-Kustner et al., 2005; Wijn et al., 2007). FAP and Gardner syndrome are caused by a large number of germinal mutations in the
The identification of mutations in
4. Supernumerary tooth formation in a mouse model
A number of mouse mutants provide insights into the supernumerary tooth formation (Takahashi et al., 2013). Several mechanisms by which supernumerary tooth might arise in mice have been proposed (Murashima-Suginami et al., 2008; Wang et al., 2009). One plausible explanation for supernumerary tooth formation is the rescue of tooth rudiments such as within the diastema region or maxillary deciduous incisor (Yamamoto et al., 2005; Murashima-Suginami et al., 2007; Lagronova-Churava et al., 2013). During early stages of mouse tooth development transient vestigial tooth buds develop in the diastema area; developing to the bud stage yet later regressing and disappear by apoptosis, or merge with the mesial crown of the adjacent first molar tooth organ (Yamamoto et al., 2005; Lagronova-Churava et al., 2013). The rudimentary maxillary incisor regressed by apoptotic elimination of mesenchymal cells (Murashima-Suginami et al., 2007). We demonstrated that
We also demonstrated that
These mouse models clearly demonstrated that it was possible to induce
5. Molecularly targeted therapy
Molecularly targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific types of cells by interfering with specific targeted molecules.
Most targeted therapies are either small moleclule or monoclonal antibodies. Small molecules are typically able to diffuse into cells and can act on target that are found inside the cells. Monoclonal antibodies usually can not penetorate the surface membrane and are directed against targets that are outside cells or on the surface of cells. Candidates for small molecules are identified in screeing the effect of thousands of test compounds on a specific target. The best candidates are then chemically modified to produce many closely related versions. Monoclonal antibody are prepared first by immunized animals such as mice with purified target moleclules.They are humanized by replacing the animal portion of the antibody with human portion. More than 40 molecularly targeted cancer therapy have been approved by the U.S Food and Drug Administration for the treatment of specific type of cancer. Many more are in clinical trials or preclinical testing (Forscher et al., 2014). Recent molecularly targeted therapy also has successfully been introduced into the treatment of several inflammatory rheumatic diseases such as rheumatoid arthritis (Mocsai et al., 2014).
Molecularly targeted therapy provides a unique tool for the delivery of previously identified signaling molecules in both time and space that may significantly augment our progress toward clinical tooth regeneration. Stimulation of the formation of a third dentition comprises an attractive concept (Figure 4). This approach is generally presented in terms of adding molecules to induce
Molecularly targeted therapy seems to be a suitable approach in tooth regeneration by stimulation of the third dentition.
The third dentition develops lingual to the permanent tooth germ (D). All impacted supernumerary teeth in this patient are located to the lingual side of the permanent teeth (white arrow) (A-C). These multiple supernumerary teeth seem to be post-permanent dentition (“third dentition”). (Takahahsi et al., 2013, copy right, In Tech)
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Underlined molecules are responsible genes for human syndromes or mutant mouse associated with supernumerary teeth
6. Conclusion
We have a chance to access the formation of the third dentition in the mouth, because the timing of the appearance of the third dentition seems to be after birth. The identification of mutations in
Acknowledgments
This work was supported by Grant-in-Aid for Scientific Research(C):22592213 and 25463081 and A-STEP (Adaptable & Seamless Technology Transfer Program through Target-driven R&D) FS stage: AS231Z01061G and AS242Z02645Q.
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