The circadian clock in enamel development

Abstract

Circadian rhythms are self-sustaining oscillations within biological systems that play key roles in a diverse multitude of physiological processes. The circadian clock mechanisms in brain and peripheral tissues can oscillate independently or be synchronized/disrupted by external stimuli. Dental enamel is a type of mineralized tissue that forms the exterior surface of the tooth crown. Incremental Retzius lines are readily observable microstructures of mature tooth enamel that indicate the regulation of amelogenesis by circadian rhythms. Teeth enamel is formed by enamel-forming cells known as ameloblasts, which are regulated and orchestrated by the circadian clock during amelogenesis. This review will first examine the key roles of the circadian clock in regulating ameloblasts and amelogenesis. Several physiological processes are involved, including gene expression, cell morphology, metabolic changes, matrix deposition, ion transportation, and mineralization. Next, the potential detrimental effects of circadian rhythm disruption on enamel formation are discussed. Circadian rhythm disruption can directly lead to Enamel Hypoplasia, which might also be a potential causative mechanism of amelogenesis imperfecta. Finally, future research trajectory in this field is extrapolated. It is hoped that this review will inspire more intensive research efforts and provide relevant cues in formulating novel therapeutic strategies for preventing tooth enamel developmental abnormalities.

Fig. 1

Microstructures of mature tooth enamel. a Incremental lines in tooth enamel, including cross striations, Retzius lines and intradian lines; b Schematic diagram of enamel rods (a) and electron microscopy images of enamel at different orientations: parallel to the rods (b) and perpendicular to the rods (c) (Adapted from Schneider et al. 2008)

Fig. 2

The life cycle of ameloblasts. a The life cycle of ameloblasts, includes the pre-maturation stage (1–3), secretory stage (4), transition stage (5-6), maturation stage (7) and post-maturation stage. Among them, maturation stage contains ruffled end ameloblast (RAs) and smooth end ameloblasts (SAs); b The energy metabolism in RA/SA transition

Fig. 3

Aligned AMELX nanoribbons act as a template for guided apatite crystal growth and serve as a precursor to enamel rods. a Enamel matrix protein deposition facilitates mineralization and calcification, with aligned Amelx nanoribbons acting as a template for guided apatite crystal growth and serving as a precursor to enamel rods. Ca²⁺ and PO₄³⁻ stabilize the nanoribbon structure by forming ion bridges between AMELX dimers (Adapted from Lacruz et al.,); b Amelx is essential for the formation of a hierarchically HAP crystal microstructure (Adapted with permission from Yang et al., 2010, copyright 2010 American Chemical Society.)

Fig. 4

The molecular mechanism of TTFLs

Fig. 5

Possible mechanisms by which circadian clocks regulate ameloblasts and facilitate amelogenesis: a The differentiation of ameloblasts; b Enamel matrix protein and enzyme secretion; c Ion transportation, cell adhesion, energy metabolism and regulation of morphology

Fig. 6

Possible mechanisms by which abnormal circadian rhythms negatively affect enamel formation: a Normal circadian rhythms facilitate normal amelogenesis, with the oscillations being well-coupled; b Dysregulation of circadian rhythms may cause delayed ameloblast differentiation (1), as well as downregulated expression of EMPs leading to reduced enamel matrix deposition (2), abnormal intercellular connections (3), ultimately resulting in delayed and defective enamel development (4)