El objetivo de este articulo es hacer una revisión bibliográfica .. en la formación del esmalte y la dentina durante la odontogenesis, como las. During odontogenesis from this stylar shelf different morphological dental traits emerge, such as cuspal talon and lobes which form the cingulum itself in anterior . odontogénesis, pueden ser eumórfico o dismórfico, único o múl- tiple, erupcionado liza una revisión bibliográfica de diferentes artículos y textos en diferentes.

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Although a big deal of dental research is being focused to the understanding of early stages of tooth development, a huge gap exist on our knowledge on how the dental hard tissues are formed and how this process is controlled daily in order to produce very complex and diverse tooth shapes adapted for specific functions.

Emerging evidence suggests that clock genes, a family of genes that controls circadian functions within our bodies, regulate also dental mineralized tissues formation. Enamel formation, for example, is subjected to rhythmical molecular signals that occur on short 24 hour periods and control the secretion and maturation of the enamel matrix.

Accordingly, gene expression and ameloblast functions are also tightly modulated in regular daily intervals. This review summarizes the current knowledge on the circadian controls of dental mineralized tissues development with a special emphasis on amelogenesis.

Circadian rhythms are generated within an organism by endogenous biological clocks driven by cyclic events [ 1 ]. The key requirement for the description of a rhythm as circadian is to show that the rhythm persists under constant conditions i.

The peripheral clocks can be entrained by the central clock or independently by other physiological stimuli such as feeding [ 2 ]. The central clock located in the brain is composed of about 20, neurons, all of which express clock genes that oscillate in synchrony [ 34 ].

Clock genes are defined by a set of criteria that include rhythm in activity or amount as well as molecular evidence of a feedback mechanism [ 5odontogenssis ].

The key mammalian clock genes are named Aryl hydrocarbon receptor nuclear translocator-like Arntl or Bmal1circadian locomoter output cycles kaput ClockPeriod1 Per1Period2 Per2Period 3 Per3and Cryptochrome 1 and 2 Cry1Cry2. Clock genes functions are regulated by feedback mechanisms consisting of an auto-regulatory ability in which specific clock proteins negatively regulate their own synthesis.

Clock genes transmit output signals that drive rhythms of gene expression in central and peripheral tissues. Evidence for a role of clock genes in circadian physiology and clock controlled gene expression comes from the studies of clock gene knockout mice. Wild-type mice will increase their locomotor activity at night as measured by wheel-running activity. This characteristic is used to assess circadian phenotypes of knockout mice.

For example, mice articilos in Per1 lose wheel-running rhythmicity when placed in constant darkness [ 7 ].

REDOE – Revista Europea de Odontoestomatologia

On the other hand, deletion of Clock and Bmal1 genes results not only in circadian disturbances, but also in metabolic abnormalities of lipid and glucose homeostasis [ 10 — 12 ]. Thus, clock gene knockout mice have profound changes in circadian rhythmicity and offer a unique experimental genetic model to analyze the link between circadian gene networks and organ physiology.

The most direct mechanism by which clock genes drive circadian gene expression is through regulation of promoter activity of clock-controlled genes CCG [ 13 ]. Recent studies in humans confirm and further specify the role of clock genes in human diseases [ 1 ].

Exciting links between peripheral organs such as the gut and the brain are being discovered [ 2 ]. Regulation of stem cells behavior is also being linked to clock genes opening a whole new area of fascinating research [ 15 ].

Most importantly, understanding how the circadian systems work may facilitate innovative treatment options for patients with untreatable diseases such as autoimmune diseases and cancer as well as for psychiatric conditions [ 16 ]. In oral health, the possibilities of clock genes involvement into patho-physiology of oral and craniofacial tissues remain largely unexplored [ 17 ].

This review summarizes the potential roles of clock genes in dental tissues formation with a special focus on enamel development. We also present hypotheses regarding the potential connections between dysregulated clock gene expression and mineralized tissues formation in general.


The tick tock of odontogenesis.

The recently hypothesized role of clock genes in regulating stem cells properties is also briefly mentioned. The diurnal variation in the synthesis of type I collagen and osteocalcin are well known [ 1819 ] supporting the hypothesis that synthesis and secretion of the matrix proteins are under circadian control. More recent studies have confirmed that osteoblast contain a peripheral clock mechanism that regulates bone volume [ 2021 ].

It has also been documented that the molecular clock, specifically the Per genes, inhibits bone formation by preventing osteoblast proliferation [ 21 ]. Of interest, Cry2 influences mostly the osteoclastic cellular component of bone while Per2 acts on osteoblast parameters [ 22 ]. Furthermore, it is recently shown that mineralization in developing bone tissue is regulated by a local circadian oscillator mechanism [ 23 ].

Thus, we can postulate that bone deposition and mineralization are under direct circadian controls. The clinical relevance of these cyclic events controlled by clock genes is currently being studied for several bone related diseases and this new knowledge may influence novel treatment options [ 24 ]. For example, the circadian clock plays a key role in obesity and diabetes which may be controlled by osteblasts released hormones [ 25 ].

In dentistry, studies elucidating the role of clock genes in alveolar bone homeostasis warrantee novel articulox discoveries in the field of orthodontics tooth movement and periodontal tissue regeneration. Dental enamel qrticulos formed during two distinct developmental stages: Ameloblasts, the cells responsible for making enamel, are specialized epithelial cells with distinct morphological characteristics that change at each developmental stage. Secretory and maturation ameloblasts are characterized by expression of artticulos stage-specific genes that perform stage-specific functions.

Besides the stage-dependent developmental control of enamel formation several observations of the enamel matrix suggest that enamel is formed incrementally. In human dental enamel for instance, there are two regularly occurring incremental markers: These lines correspond to what was, at precise points in time during the secretory stage of amelogenesis, the enamel surface.

Between the SR and running parallel with them are distinct growth lines known as cross-striations Fig. Cross-striations delineate the amount of enamel deposited in a single day [ 2930 ].

The Tick Tock of Odontogenesis

Enamel cross-striations occur because of a circadian rhythm of ameloblast activity [ 2731 ]. Similar growth lines have been showed recently in mouse enamel as well [ 32 ]. Dental pulp is devoid of staining in both incisors and molars A. Odontoblasts in first molars are strongly stained for PER2 A, black arrowheads. PER2 proteins are also articylos in the nucleus of odontogfnesis and osteoclasts in the alveolar bone C, white arrows.

Black lines in figure F indicate the enamel cross striations in human tooth enamel. Ten cross striations are visualized between two successive Striae of Retzius perpendicular lines.

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At the cellular level, we have shown that clock proteins are strongly expressed in pre-ameloblasts and differentiated ameloblasts throughout amelogenesis both in human embryonic teeth Fig. Clock genes products are detected specifically in ameloblasts and their expression levels and localization alternates following circadian rhythms.

In addition, melatonin receptors, key regulators of the circadian functions, are also differentially expressed in ameloblasts aritculos 33 ]. We have also recently published that there are daily variations in the rate of production and secretion odontogeensis enamel proteins between early odonttogenesis and late afternoon suggesting that enamel protein secretion is under circadian control [ 27 ] Fig.

Enamel proteins secretion peaks at around 8pm and follows a circadian pattern. We have also evaluated RNA oscillations of clock genes and amelogenin and enamelin in teeth of mice kept under normal LD cycles at two time points: This preliminary data shows that Per2 and amelogenin expression peaks at 10pm with minimum expression at 10am.

In contrast, we have not detected any significant difference qrticulos enamelin expression. It is possible that enamelin is not under circadian control. Of significance, amelogenin expression still oscillates under DD conditions, however in less extend and with a slight shift in peak times [ 31 ].

In vitro studies have also confirmed that amelogenin expression is modulated by clock genes [ 313435 ] Fig. Consistent with the above findings, our preliminary analysis of Per2 knock-out teeth show abnormal enamel matrix formation unpublished. Our data also suggest that Kallikrein 4 Klk4a key gene artichlos regulates enamel maturation, might be under circadian control [ 31 ]. Taken together the above-discussed data, we postulate that enamel matrix production and maturation is closely controlled by selectively regulating some of enamel matrix proteins encoding genes.


Different amounts of proteins secreted in rat enamel are measured at different time points A Amelogenin RNA expression levels in developing mouse molars are higher at night time compare to day time. Most of BMAL1 proteins are localized in the cytoplasm at 8 am and then in the nucleus of ameloblasts at 8 pm G. In contrast, PER2 proteins are found in the nucleus at 8 am and in the cytoplasm of ameloblasts at 8 pm H. Clock genes expression is also found synchronized in two other epithelial tissues with high similarities with ameloblasts, i.

We also found that genes involved in the calcium and phosphate metabolism such as calbidin-D28K a calcium binding proteincarbonic anhydrase 2 Car2and alkaline phospatase oscillate in regular daily intervals in kidney cells suggesting that these genes might be functional targets of clock genes. Furthermore, expression of calbidin-D28K and alkaline phospatase is altered in Per2 knock-out mice kidney Fig.

It is then logical to hypothesize that these genes may also be targets of the circadian clock CCG in ameloblasts.

Consistently with our hypothesis clock genes odontogenessi mice Per2 Artichlos show also defects of enamel mineralization unpublished data. However, the precise mechanisms of calcium regulation in ameloblasts remain to be elucidated. CCG control of enamel related genes is suggested to be direct or indirect through the circadian regulation of key transcription factors as we showed for Runx2 [ 34 ].

Recently, another group showed that Runx2 is under circadian control in the suprachiasmatic nucleus and functions in the control of rhythmic behavior [ 36 ]. More studies are needed to fully comprehend the complex circadian controls that regulate enamel formation. Nevertheless, we can postulate that the ameloblast circadian clock plays significant roles in enamel atticulos, maturation and mineralization.

Similar to enamel, dentin is formed incrementally suggesting the involvement of a circadian clock mechanism during dentinogenesis.

The numbers of short-period incremental lines observed in enamel or dentin between sequentially administered dyes correspond to the number of days between successive administrations [ 38 ].

Circadian rhythms have been demonstrated using 3 H-proline tracers that label collagen in dentin formation [ 39 ]. Twice as much collagen is secreted during the daylight 12 h as during the night time 12 h. At the cellular level, we recently showed evidence that odontoblasts express clock proteins [ 8 ].

Consistently, Ohtsuka-Isoya et al. These studies suggest that dentin, similar to bone and enamel, is controlled by a circadian clock mechanism. However, very little is known on the molecular artiiculos mechanisms that regulate dentin formation. It has been described that human cementum is formed incrementally [ 41 ] and we found that periodontal ligament PDL cells differentially express clock proteins [ 8 ] Fig.

Odontogeensis cementoblasts odontogenesiis of staining Fig. It is possible, that once cementum formation is completed clock expression is turned off in cementoblasts. Alternatively, species or teeth differences may exist. ERM are hypothesized to play a role in periodontal ligament regeneration. Further studies are needed to elucidate the potential links between clock genes and periodontal maintenance and turn over.

A surpassingly finding of our analysis of clock gene expression in tooth is a strong expression of clock genes in areas rich in stem cells. For example, ERM cells, which are considered as dormant progenitor cells [ 42 ], show articklos strongest staining among all other cells in PDL Fig.

Clock proteins are also strongly expressed by dental epithelium stem cells at the incisor cervical root area [ 8 ]. Of interest, clock genes mutants show variations in incisor size, being always odomtogenesis in Per2 knockout mice unpublished. Similar to dental epithelia, hair cells express clock genes [ 43 ]. Indeed, clock genes modulate the human hair cycle clock independently of the brain suggesting that a peripheral hair clock also exists [ 4445 ].