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As the outermost layer of the tooth crown, dental enamel is the most mineralized tissue in mammals, consisting of hydroxyapatite crystallites separated by long and narrow nanochannels. A major challenge in dentistry is how various molecules can be infiltrated into these nanopores in an efficient and controlled way. Here we show a robust method to transport various ions of interest, such as fluoride (F-), potassium (K+), calcium (Ca++), and sodium (Na+), into these nanopores by electrokinetic flows. It is verified by fluorescence microscopy, laser-scanning confocal microscopy, mass spectrometry, and ion selective electrode technique. Different ions are demonstrated to infiltrate through the entire depth of the enamel layer (~1 mm), which is significantly enhanced penetration compared with diffusion-based infiltration. Meanwhile, transport depth and speed can be controlled by infiltration time and applied voltage. This is the first demonstration of reliably delivering both anions and cations into the enamel nanopores. This technique opens opportunities in caries prevention, remineralization, tooth whitening, and nanomedicine delivery in clinical dentistry, as well as other delivery challenges into various biomaterials such as bones. [ABSTRACT FROM AUTHOR]

Species-specific cusp patterns result from the iterative formation of enamel knots, the epithelial signaling centers, at the future cusp positions. The expressions of fibroblast growth factors (FGFs), especially Fgf4, in the secondary enamel knots in the areas of the future cusp tips are generally used to manifest the appearance of species-specific tooth shapes. However, the mechanism underlying the predictive role of FGFs in species-specific cusp patterns remains obscure. Here, we demonstrated that gerbils, which have a lophodont pattern, exhibit a striped expression pattern of Fgf4, whereas mice, which have a bunodont pattern, have a spotted expression pattern, and these observations verify the predictive role of Fgf4 in species-specific cusp patterns. By manipulating FGFs' signaling in the inner dental epithelium of gerbils, we provide evidence for the intracellular participation of FGF signaling, specifically FGF4 and FGF20, in Rac1- and RhoA-regulated cellular geometry remolding during the determination of different cusp patterns. Our study presents a novel explanation of how different FGF expression patterns produce different cusp patterns and implies that a conserved intracellular FGF-GTPase signaling module might represent an underlying developmental basis for evolutionary changes in cusp patterns. [ABSTRACT FROM AUTHOR]

Previous studies show that both activin and Bmp4 act as crucial mesenchymal odontogenic signals during early tooth development. Remarkably, mice lacking activin-βA ( Inhba-/-) and mice with neural crest-specific inactivation of Bmp4 ( Bmp4ncko/ncko) both exhibit bud-stage developmental arrest of the mandibular molar tooth germs while their maxillary molar tooth germs completed morphogenesis. In this study, we found that, whereas expression of Inhba and Bmp4 in the developing tooth mesenchyme is independent of each other, Bmp4ncko/nckoInhba-/- compound mutant mice exhibit early developmental arrest of all tooth germs. Moreover, genetic inactivation of Osr2, a negative regulator of the odontogenic function of the Bmp4-Msx1 signaling pathway, rescues mandibular molar morphogenesis in Inhba-/- embryos. We recently reported that Osr2 and the Bmp4-Msx1 pathway control the bud-to-cap transition of tooth morphogenesis through antagonistic regulation of expression of secreted Wnt antagonists, including Dkk2 and Sfrp2, in the developing tooth mesenchyme. We show here that expression of Dkk2 messenger RNAs was significantly upregulated and expanded into the tooth bud mesenchyme in Inhba-/- embryos in comparison with wild-type littermates. Furthermore, in utero treatment with either lithium chloride, an agonist of canonical Wnt signaling, or the DKK inhibitor IIIC3a rescued mandibular molar tooth morphogenesis in Inhba-/- embryos. Together with our finding that the developing mandibular molar tooth bud mesenchyme expresses significantly higher levels of Dkk2 than the developing maxillary molar tooth mesenchyme, these data indicate that Bmp4 and activin signaling pathways converge on activation of the Wnt signaling pathway to promote tooth morphogenesis through the bud-to-cap transition and that the differential effects of loss of activin or Bmp4 signaling on maxillary and mandibular molar tooth morphogenesis are mainly due to the differential expression of Wnt antagonists, particularly Dkk2, in the maxillary and mandibular tooth mesenchyme. [ABSTRACT FROM AUTHOR]

Tooth agenesis is a common structural birth defect in humans that results from failure of morphogenesis during early tooth development. The homeobox transcription factor Msx1 and the canonical Wnt signaling pathway are essential for "bud to cap" morphogenesis and are causal factors for tooth agenesis. Our recent study suggested that Msx1 regulates Wnt signaling during early tooth development by suppressing the expression of Dkk2 and Sfrp2 in the tooth bud mesenchyme, and it demonstrated partial rescue of Msx1 -deficient molar teeth by a combination of DKK inhibition and genetic inactivation of SFRPs. In this study, we found that Sostdc1/Wise, another secreted Wnt antagonist, is involved in regulating the odontogenic pathway downstream of Msx1. Whereas Sostdc1 expression in the developing tooth germ was not increased in Msx1 -/- embryos, genetic inactivation of Sostdc1 rescued maxillary molar, but not mandibular molar, morphogenesis in Msx1 -/- mice with full penetrance. Since the Msx1 -/- ; Sostdc1 -/- embryos exhibited ectopic Dkk2 expression in the developing dental mesenchyme, similar to Msx1 -/- embryos, we generated and analyzed tooth development in Msx1 -/- ; Dkk2 -/- double and Msx1 -/- ; Dkk2 -/- ; Sostdc1 -/- triple mutant mice. The Msx1 -/- ; Dkk2 -/- double mutants showed rescued maxillary molar morphogenesis at high penetrance, with a small percentage also exhibiting mandibular molars that transitioned to the cap stage. Furthermore, tooth development was rescued in the maxillary and mandibular molars, with full penetrance, in the Msx1 -/- ; Dkk2 -/- ; Sostdc1 -/- mice. Together, these data reveal 1) that a key role of Msx1 in driving tooth development through the bud-to-cap transition is to control the expression of Dkk2 and 2) that modulation of Wnt signaling activity by Dkk2 and Sostdc1 plays a crucial role in the Msx1-dependent odontogenic pathway during early tooth morphogenesis.

As the outermost layer of the tooth crown, dental enamel is the most mineralized tissue in mammals, consisting of hydroxyapatite crystallites separated by long and narrow nanochannels. A major challenge in dentistry is how various molecules can be infiltrated into these nanopores in an efficient and controlled way. Here we show a robust method to transport various ions of interest, such as fluoride (F - ), potassium (K + ), calcium (Ca ++ ), and sodium (Na + ), into these nanopores by electrokinetic flows. It is verified by fluorescence microscopy, laser-scanning confocal microscopy, mass spectrometry, and ion selective electrode technique. Different ions are demonstrated to infiltrate through the entire depth of the enamel layer (~1 mm), which is significantly enhanced penetration compared with diffusion-based infiltration. Meanwhile, transport depth and speed can be controlled by infiltration time and applied voltage. This is the first demonstration of reliably delivering both anions and cations into the enamel nanopores. This technique opens opportunities in caries prevention, remineralization, tooth whitening, and nanomedicine delivery in clinical dentistry, as well as other delivery challenges into various biomaterials such as bones.