Molecular Basis of Tooth Development Related to Dental Defects Causing Tooth Loss

RELATED TO DENTAL DEFECTS CAUSING TOOTH LOSS Tooth agenesis is the most prevalent craniofacial congenital malformation in humans. Up to 25% of the population may lose at least one third molar. Agenesis of other permanent teeth, excluding third molars, ranges from 1.6 to 9.6%, depending on the population studied. Primary dentition may also be affected, but with lower prevalence (from 0.5 to 0.9%) (Vastardis, 2000). As a rule, when a primary tooth does not develop, the secondary tooth is also missing. The majority of persons with hypodontia (80%) lack only one or two teeth (Lidral and Reising, 2002), permanent second premolars and upper lateral incisors being predominantly affected (Symons et al., 1993). However, about 1% (0.08-1.1%) of the population suffers from oligodontia—the agenesis of more than 6 teeth (Schalk-Van der Weide et al., 1992; Stockton et al., 2000; Gabris et al., 2001). Loss of all teeth is known as anodontia. How tooth loss comes about is thus an important question. Tooth development is a complex process that involves signaling interplay between the embryonic stomodeal epithelium facing the oral cavity and the underlying neural-crest-derived mesenchyme. First, signaling molecules expressed in the dental epithelium signal to the underlying mesenchyme, establishing the dental mesenchyme (dental placode stage). Subsequently, the odontogenic potential shifts to the dental mesenchyme, and mesenchymal factors direct tooth bud morphogenesis, including formation of the primary enamel knot signaling center that directs future tooth crown shaping. Odontogenic epithelio-mesenchymal interactions repeatedly recruit basic organogenic cascades involving Fgf, Bmp, Shh, and Wnt signaling. Any disturbances in the tightly balanced signaling cascades may result in dental defects, including changes in tooth number, size, morphology, and cytodifferentiation. Lessons from animal models, especially the mouse, are crucial for the understanding of the basic genetic principles of hypodontia (Fleischmannová et al., 2008). On the surface, it would appear difficult to mimic a complex hypodontia phenotype in an oligodont animal with only one tooth generation. However, despite these substantial differences between the mouse and human dentitions, early stages of tooth development are largely similar in both species, and the basic principles of tooth development originally discovered in the mouse have been confirmed in humans. Exploiting the well-established techniques of mouse molecular genetics, investigators have identified several knockouts that display a tooth agenesis phenotype. Tooth development is arrested at the bud stage in Pax9, Msx1, Pitx2, Gli2/3, p63, and Lef1 knockout mice, while in the case of the Dlx1/2 knockout, maxillary molars alone are lost. In contrast, Activin a deficiency results in an inverse phenotype, with loss of the mandibular molars and incisors and preservation of the maxillary molars. Disruption of several of these same molecules has been confirmed to result in tooth agenesis in humans as well. ABSTRACT Tooth agenesis may originate from either genetic or environmental factors. Genetically determined hypodontic disorders appear as isolated features or as part of a syndrome. Msx1, Pax9, and Axin2 are involved in nonsyndromic hypodontia, while genes such as Shh, Pitx2, Irf6, and p63 are considered to participate in syndromic genetic disorders, which include tooth agenesis. In dentistry, artificial tooth implants represent a common solution to tooth loss problems; however, molecular dentistry offers promising solutions for the future. In this paper, the genetic and molecular bases of non-syndromic and syndromic hypodontia are reviewed, and the advantages and disadvantages of tissue engineering in the clinical treatment of tooth agenesis are discussed.