A Promising Future Ahead for Personalized Endodontics

By Renato M. Silva, DDS, MS, PhD

Understanding pulpal and periapical physiology and the underlying disease mechanisms involved in tissue inflammation, repair and regeneration is key to the advancement of endodontics.

Molecular and cellular biology plays an important role in scientific discoveries as tools to elucidating key players in disease pathophysiology and identifying targets for the development of prevention and treatment strategies. One of the main challenges in endodontics is still to determine proper diagnosis as the basis for adequate treatment.

It has become clear that individual variability may play a role in the response to endodontic treatment. Given research advances, dentists need to consider the potential for individualized or personalized dentistry, customized for an individual patient, where biological information acquired through a genetic test or biomarker profiling may directly influence diagnosis, treatment and, eventually, pulpal and periapical disease prevention.

Major cells of the immune system (monocytes, macrophages, neutrophils, basophils, dendritic cells, mast cells, T-cells, and B-cells) are important players in pulpal and periapical inflammation as well as wound healing. DNA, RNA and proteins are responsible for orchestrating all of the cellular functions and processes in our body. Wound healing and tissue regeneration are complex processes that involve cellular communication and activation of signaling molecules, extracellular matrix components, remodeling enzymes, cellular adhesion molecules, growth factors, cytokines and chemokines.

Cytokines and chemokines are inflammatory mediators that act as alarm signals in acute and chronic inflammation, allowing the cells to communicate with each other prompting activation of the immune system to fight microorganisms and their byproducts. A good example is the participation of receptor activator nuclear factor kappa B ligand (RANKL) and osteoprotegerin (OPG) in apical tissue destruction and healing. RANKL binding to the receptor RANK present on the surface of preosteoclasts drives osteoclast maturation and activation, whereas OPG, the naturally occurring inhibitor of RANKL, is a decoy receptor that prevents RANK-RANKL engagement thereby inhibiting osteoclast activation (1, 2). Apical periodontitis presents heterogeneous patterns of RANKL and OPG expression(2). Inhibition of the RANKL-RANK system has become a therapeutic target for the treatment of osteoporosis (3) and has been explored in endodontics aiming to reduce periapical tissue damage (2).

However, the molecular signatures and functional pathways underlying these processes in the pulpal and periapical environment remain unclear requiring further research. From a clinical perspective, the ability to distinguish between a progressive lesion from a stable lesion that is undergoing regression and healing is critical to determine the need of additional treatment interventions.  In the near future genetic tests performed chairside in the office may help endodontists make improved, patient-centered treatment decisions. Questions such as pulp capping/pulpotomy versus conventional endodontic treatment or non-surgical endodontic retreatment versus periapical surgery are still controversial topics in Endodontics.

Development and advancement of personalized dentistry strategies involve understanding the immune system, effector cells and microorganisms, and the identification of relevant biochemical markers of potential usefulness for clinical management of oral diseases, including pulpal and periapical diseases. Single nucleotide polymorphisms (SNPs), DNA methylation and microRNAs in relevant genes may impact gene/protein function, contributing to individual predisposition to pulpal inflammation and/or apical periodontitis development (4-6).  SNPs are single base substitutions that are present in the genome and occur in 1% of the general population. Their effects on the encoded protein depend on which region of the gene the SNP is located (i.e., coding versus noncoding regions) (7). DNA methylation is a type of epigenetic modification that can modify gene expression patterns without altering the DNA sequence, comprising a tool that cells use to lock genes in the “off” position (6). MicroRNAs (miRNAs) are small non-coding RNAs with the capability of modulating gene expression at the post-transcriptional level either by inhibiting messenger RNA (mRNA) translation or by promoting mRNA degradation(8).

It is also important for us to learn how to stimulate the body’s natural ability to heal and regenerate.

During the last decade, there have been great strides in dental pulp revascularization and regeneration therapies; however, periapical tissue regeneration still requires attention. Interestingly, the literature shows that mesenchymal stem cells present in inflamed periapical tissues can be a good source to promote tissue repair, anti-inflammatory, immunosuppressive and proangiogenic effects(9).

Endodontic research encompasses multiple disciplines. In the pulpal and periapical environment, the interaction between bacteria and host cells affect the activity of one another.  The molecular strategies used by microorganisms to interact with the host can be unique warranting additional research in endodontics.

Most recently, a major focus in cancer and inflammatory disease research reflects on understanding the recruitment of leukocytes to promote healing and repair. Regulatory T-cells (Tregs) comprise a CD4+FOXp3 +T-cell subset with a unique ability to regulate other leukocyte functions avoiding excessive immune activation and its pathological consequences. Recent advances in controlled-release technology allows for a selective chemoattraction of Tregs to periodontal tissues, attenuating tissue destruction by controlling the local inflammatory immune response and stimulating a pro-reparative environment (10).

In conclusion, the discovery of new target genes and pathways may point to promising new options for endodontic diagnosis while future research on biologic agents as immune modulators may lead to improved, precision-based therapies for pulpal and periapical diseases.

References:

1. Teitelbaum SL. Bone resorption by osteoclasts. Science. 2000;289(5484):1504-8.
2. Menezes R, Garlet TP, Letra A, Bramante CM, Campanelli AP, Figueira Rde C, et al. Differential patterns of receptor activator of nuclear factor kappa B ligand/osteoprotegerin expression in human periapical granulomas: possible association with progressive or stable nature of the lesions. J Endod. 2008;34(8):932-8.
3. Matsumoto T, Endo I. RANKL as a target for the treatment of osteoporosis. J Bone Miner Metab. 2021;39(1):91-105.
4. de Souza LC, Cavalla F, Maili L, Garlet GP, Vieira AR, Silva RM, et al. WNT gene polymorphisms and predisposition to apical periodontitis. Sci Rep. 2019;9(1):18980.
5. Cavalla F, Letra A, Silva RM, Garlet GP. Determinants of Periodontal/Periapical Lesion Stability and Progression. J Dent Res. 2021;100(1):29-36.
6. Campos K, Franscisconi CF, Okehie V, de Souza LC, Trombone AP, Letra A, et al. FOXP3 DNA methylation levels as a potential biomarker in the development of periapical lesions. J Endod. 2015;41(2):212-8.
7. Johnston HR, Keats BJB, Sherman SL. 12 – Population Genetics. In: Pyeritz RE, Korf BR, Grody WW, editors. Emery and Rimoin’s Principles and Practice of Medical Genetics and Genomics (Seventh Edition): Academic Press; 2019. p. 359-73.
8. Correia de Sousa M, Gjorgjieva M, Dolicka D, Sobolewski C, Foti M. Deciphering miRNAs’ Action through miRNA Editing. Int J Mol Sci. 2019;20(24).
9. Liao J, Al Shahrani M, Al-Habib M, Tanaka T, Huang GT. Cells isolated from inflamed periapical tissue express mesenchymal stem cell markers and are highly osteogenic. J Endod. 2011;37(9):1217-24.
10. Garlet GP, Sfeir CS, Little SR. Restoring host-microbe homeostasis via selective chemoattraction of Tregs. J Dent Res. 2014;93(9):834-9.