MicroRNAs and Periodontal Homeostasis

Abstract

MicroRNAs (miRNAs) are a group of small RNAs that control gene expression in all aspects of eukaryotic life, primarily through RNA silencing mechanisms. The purpose of the present review is to introduce key miRNAs involved in periodontal homeostasis, summarize the mechanisms by which they affect downstream genes and tissues, and provide an introduction into the therapeutic potential of periodontal miRNAs. In general, miRNAs function synergistically to fine-tune the regulation of biological processes and to remove expression noise rather than by causing drastic changes in expression levels. In the periodontium, miRNAs play key roles in development and periodontal homeostasis and during the loss of periodontal tissue integrity as a result of periodontal disease. As part of the anabolic phase of periodontal homeostasis and periodontal development, miRNAs direct periodontal fibroblasts toward alveolar bone lineage differentiation and new bone formation through WNT, bone morphogenetic protein, and Notch signaling pathways. miRNAs contribute equally to the catabolic aspect of periodontal homeostasis as they affect osteoclastogenesis and osteoclast function, either by directly promoting osteoclast activity or by inhibiting osteoclast signaling intermediaries or through negative feedback loops. Their small size and ability to target multiple regulatory networks of related sets of genes have predisposed miRNAs to become ideal candidates for drug delivery and tissue regeneration. To address the immense therapeutic potential of miRNAs and their antagomirs, an ever growing number of delivery approaches toward clinical applications have been developed, including nanoparticle carriers and secondary structure interference inhibitor systems. However, only a fraction of the miRNAs involved in periodontal health and disease are known today. It is anticipated that continued research will lead to a more comprehensive understanding of the periodontal miRNA world, and a systematic effort toward harnessing the enormous therapeutic potential of these small molecules will greatly benefit the future of periodontal patient care.

Keywords: alveolar bone; nanoparticle; osteoblast; osteoclast; periodontium; small RNA.

Figure 1.

Microarray analysis of microRNA (miRNA) expression in control and osteogenesis-induced PDLSCs. For this study, PDLSCs were cultured under osteogenic induction conditions for 12 d and compared with controls. (A) Heat map of miRNA expression profiling. miRNAs with a significant level of up- or downregulation (P < 0.01) were identified using Student’s t test. Individual up- and downregulated genes are listed in Table 1. (B) quantitative Reverse Transcriptase (qRT)polymerase chain reaction verification of miR-27, miR-29, and miR-138 expression in control and osteogenesis-induced PDLSCs. *P < 0.05.

Figure 2.

MicroRNA (miRNA)–mediated regulation of osteoblastogenesis from mesenchymal stem cells (MSCs). This sketch illustrates the role of miRNAs during the differentiation of mesenchymal stem cells into osteoblasts and osteocytes under physiological and inflammatory conditions or when exposed to mechanical stress. Note that by affecting different types of targeting genes, miRNAs either promote or inhibit osteoblastogenesis.

Figure 3.

MicroRNA (miRNA)–mediated regulation of osteoclastogenesis. Here we illustrate the effects of miRNAs during the 4 stages of osteoclastogenesis from monocytes to preosteoclasts and then from mature osteoclasts to activated osteoclasts. At each point of transition, microRNAs either promote or inhibit osteoclastogenesis through their targeting genes.

Figure 4.

Putative model illustrating the role of microRNAs (miRNAs) and WNT signaling and alveolar bone homeostasis. In this model, inflammatory conditions downregulate miRNA subsets, which leads to an upregulation of some WNT inhibitors, a reduction in osteogenesis, and an increase in bone resorption. Therapy with selected miRNAs and miRNA mimics in turn may downregulate WNT inhibitors and upregulate WNT signaling, which then would lead to new bone formation and a decrease in bone resorption.