Implications of the circadian clock in implant dentistry

Abstract

Circadian rhythms are approximately 24-h cell-autonomous cycles driven by transcription and translation feedback loops of a set of core circadian clock genes, such as circadian locomoter output cycles kaput (Clock), brain and muscle arnt-like protein-1 (Bmal1), period (Per), and cryptochrome (Cry). The genetic clockwork of these genes produces circadian rhythms in cells throughout the body, including the craniofacial region. During development, dento-alveolar bone tissue formation could be regulated by site-specific circadian patterns. Studies using knockout mice and mesenchymal stem cells (MSCs) to evaluate clock genes revealed regulatory effects of clock function on bone remodeling, suggesting involvement of the circadian clockwork in osseointegration of titanium implants. Indeed, rough surface titanium modulates specific clock genes, Neuronal PAS domain protein-2 (Npas2) and Per, in MSCs to facilitate osseointegration. Further understanding of the bone clock machinery associated with biomaterial surface properties might improve preoperative diagnosis for dental implant treatments.

The Influence of Dental Implants on the Circadian Clock and the Role of Melatonin in the Oral Cavity

“…In the lack of CLOCK, NPAS2 is a replacement for forming heterodimer NPAS2:BMAL1. 15 The second circadian clock regulatory loop includes the retinoic acid-related orphan receptor (ROR) α and RORγ, and the REV-ERBα and REV-ERBβ genes. The CLOCK:BMAL1 heterodimer initiates their transcription by binding to the E-box elements of their promoters.…”

“…Mesenchymal stem cells are adult stem cells with multipotent ability to differentiate and could be isolated from tooth tissue, bone marrow, amniotic fluid, adipose tissue, and additional sources. 15 The expression profile of genes linked with osteogenic mesenchymal stem cell differentiation shows that molecular circadian rhythm regulates mesenchymal stem cell differentiation. Circadian clock transcription factors control the expression of core clock genes and other clock-controlled genes (CCG).…”

“…The positioning of titanium implants creates a distinct cellular condition that could increase the osteogenic differentiation of bone marrow mesenchymal stem cells. 15 Thus, PER1 gene expression is reduced in stromal bone marrow cells due to titanium-based biomaterials, essential for osseointegration. 6 Furthermore, mesenchymal stem cells susceptible to various titanium substances in vitro improved osteogenic differentiation.…”

“…6 Furthermore, mesenchymal stem cells susceptible to various titanium substances in vitro improved osteogenic differentiation. 15 Almost 30% of genes show circadian oscillations, 1, 18 and among them in the maxillo-mandibular complex is osteocalcin. Although the peripheral bone circadian clock function has not been thoroughly investigated, implant-induced microenvironmental change significantly affects NPAS2 and PER2 gene expression regulation or dysregulation in peri-implant tissue (Table 1).…”

“…15, 30 The expression of NPAS2 in interface tissue could therefore be the basis of osseointegration. 15 The surface of titanium biomaterials is subject to oxidation, and the microenvironment around titanium biomaterials is hypoxic. Therefore, there is an increase in the signaling of hypoxia-induced factor (HIF)-1α in mesenchymal stem cells exposed to titanium biomaterials.…”