Feasibility of Molecularly Targeted Therapy for Tooth Regeneration - New Trends in Tissue Engineering and Regenerative Medicine - page 57

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 RUNX2
(Mundlos et al., 1997). There is a wide spectrum of phenotypic variability ranging from the
full-blown phenotype to an isolated dental phenotype characterized by supernumerary tooth
formation and/or the delayed eruption of permanent teeth in CCD (Takahashi et al., 2008).
Runx2 -deficient mice were found to exhibit lingual buds in front of the upper molars, and these
were much more prominent than in wild-type mice (Aberg et al., 2004). These buds presumably
represent the mouse secondary dentition, and it is likely that RUNX2 acts to prevent the
formation of these buds. Runx2 regulates the proliferation of cells and may exert specific
control on the dental lamina and formation of successive dentitions. Runx2 heterozygous
mutant mice mostly phenocopied the skeletal defects of CCD in humans, but with no super‐
numerary tooth formation (Otto et al., 1997). Notably, in Runx2 homozygous and heterozygous
mouse upper molars, a prominent epithelial bud regularly presents. This epithelial bud
protrudes lingually with active Shh signaling, and it may represent the extension of the dental
lamina for successional tooth formation in mice. Hence, although Runx2 is required for primary
tooth development, it prevents the growth of the dental lamina and successional tooth
formation (Otto et al., 1997).
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 (Chi‐
menos-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 Apc gene (Groden et al.,
1991). Apc is a tumor suppressor gene involved in the down-regulation of free intracellular ß-
catenin, the major signal transducer of the canonical Wnt signaling pathway (Groden et al.,
1991). Approximately 11-27% of patients have supernumerary teeth, but, so far, no specific
codon mutation of the Apc gene has been found to correlate with supernumerary teeth.
The identification of mutations in RUNX2 causing an isolated dental phenotype in CCD and
in Apc causing FAP has attracted attention as a possible route towards inducing de novo tooth
formation.