The circadian clock in oral health and diseases

Abstract

Most physiological processes in mammals display circadian rhythms that are driven by the endogenous circadian clock. This clock is comprised of a central component located in the hypothalamic suprachiasmatic nucleus and subordinate clocks in peripheral tissues. Circadian rhythms sustain 24-hour oscillations of a large number of master genes controlling the correct timing and synchronization of diverse physiological and metabolic processes within our bodies. This complex regulatory network provides an important communication link between our brain and several peripheral organs and tissues. At the molecular level, circadian oscillations of gene expression are regulated by a family of transcription factors called "clock genes". Dysregulation of clock gene expression results in diverse human pathological conditions, including autoimmune diseases and cancer. There is increasing evidence that the circadian clock affects tooth development, salivary gland and oral epithelium homeostasis, and saliva production. This review summarizes current knowledge of the roles of clock genes in the formation and maintenance of oral tissues, and discusses potential links between "oral clocks" and diseases such as head and neck cancer and Sjögren's syndrome.

Keywords: Sjögren’s syndrome; autoimmune diseases; clock genes; oral cancer; salivary glands; tooth.

Figure 1.

Schematic representation of the central mammalian circadian clock network. The oscillator consists of 2 interlocked negative feedback loops. In the core negative feedback loop, the repressors (PER and CRY proteins) inactivate the activators (BMA and CLOCK proteins). In the other negative feedback loop, the activators repress their own transcription expression through an inhibition mediated by REV-ERB and ROR proteins.

Figure 2.

Immunohistochemistry of CLOCK and PER2 proteins in post-natal days 4 and 21 mouse heads. (A) CLOCK protein expression is detected in the developing first molars and oral epithelium (OE) at the palate. (B,C) Higher magnifications showing that the nuclei (arrows) of ameloblasts (Am) and odontoblasts (Od) show strong CLOCK expression relative to the dental pulp cells. PER2 shows relatively weak expression in periodontal dental ligament (PDL) cells when compared with odontoblast expression (D). Epithelial rests of Malassez (ERM) show strong expression of the PER2 protein within the PDL space (D, black arrows). PER2 proteins are also detected in the nuclei of osteoblasts and osteoclasts in the alveolar bone (D, white arrows). No PER2 protein expression is detected in cementoblasts (D, white arrowheads). PER2 protein is also strongly detected in junctional epithelium (JE) but not in oral sulcular epithelium (OSE) (E). Scale bars = 200 μm in A, 100 μm in B, 20 μm in C, D, and E.

Figure 3.

The circadian clock of salivary glands regulates Aqp5 and cytokine expression and salivary flow levels. Circadian rhythms are detected in human unstimulated salivary flow (A). Immunohistochemistry results showed that the CLOCK protein is expressed in the nuclei of mucous acini (MA) and serous acini (SA), and in the epithelial cells of the ducts in mouse salivary glands. Expression was much weaker in duct cells. Scale bars = 20 μm. (B). AQP5 mRNA levels in HEK293 cells are up-regulated after transient transfection with a Bmal1 over-expression vector. All time interval calculations are based at the indicated zeitgeber (ZT; a zeitgeber is any external or environmental cue that entrains, or synchronizes, an organism’s biological rhythms) time; ZT 0 was considered to be 2 hrs after cell-cycle synchronization. The experiments were repeated 3 times, and 1 representative experiment is presented (*p < .05; compared with 0 hr). (C). The saliva level is higher in Per2 knock-out mice than in wild-type mice after simulation (D).

Figure 4.

Emerging evidence strongly suggests that alterations of the circadian clock are directly or indirectly linked to an increasing list of chronic illnesses. This illustration summarizes the reported connections of the circadian clock with chronic diseases. Please note that patients can develop more than one of these diseases (co-morbidities). Modified from Kondratova and Kondratov, 2012.

Figure 5.

This illustration summarizes the list of the known inputs and outputs of the circadian clock system. It also shows the most well-characterized interactions between the central and peripheral clocks. We have included tooth mineralization and saliva production as novel outputs in this list. Modified after Garaulet and Madrid, 2009.