A New Era in the Treatment of Periodontal Disease

Many dental hygienists are aware of new information related to proteomics, salivary diagnostics and bioactive lipids as anti-inflammatory mediators, as well as the potential of these scientific advances to change our clinical approach when treating periodontal diseases. These exciting developments are based in molecular medicine, “a science that seeks to comprehend disease causes and mechanisms at the molecular level, and to apply this basic research to the prevention, diagnosis and treatment of diseases and disorders.”¹ The purpose of this article is to define and discuss these innovations and their potential application to dental hygiene practice in the future.

Periodontitis is an inflammatory disease that results from the complex interaction between infectious agents found in the microbial biofilm and host factors. The initiation and progression of periodontal disease is mediated by various protein and lipid molecules, known as inflammatory mediators, that are released by inflammatory and immune cells in response to the biofilm accumulation on the teeth. Scientists are studying proresolving lipid mediators as a means of reversing inflammation in periodontal disease and examining the role of proteins asbiomarkers of periodontal diseases.^2,3 Ensuing discoveries will be important in the future of periodontal disease diagnosis, prevention and treatment.

Bioactive Lipids as Proresolving Inflammatory Mediators

In periodontitis, it is the host response trying to eliminate the biofilm that actually destroys the periodontium, rather than direct actions of the bacteria. One theory is that the inflammatory response may be overly robust in individuals who are susceptible to the disease.² Dental hygienists and dentists have been taught that the resolution of inflammation is a passiveprocess; a decay of proinflammatory mediators followed by healing. The assumption was that the proinflammatory mediators went away because the insult was gone. Now, researchers are finding that resolution of inflammation is an active process in which proresolving lipid mediators play an important role.² According to Thomas Van Dyke, DDS, PhD, vice president of Clinical and Translational Research and chair, Department of Periodontology at The Forsyth Institute, research related to proresolving lipid mediators is changing longstanding beliefs about the microbial biofilm and inflammation in periodontal disease. In periodontal disease, bacteria in biofilm stimulate the innate immune response; chronic inflammation stems from a perceived failure of the host to resolve the insult, he stated. A susceptible individual is one with a higher inflammatory response to the biofilm with over-expression of proinflammatory pathways that foster the host response. Controlling inflammation is just as important as removing bacteria in susceptible individuals. Another way of looking at chronic periodontal inflammation is that excessive inflammation may result from a failure of resolution pathways as much as over-expression of proinflammatory pathways, Van Dyke adds.

Acute inflammation is protective; pathogens are eliminated, and return to homeostasis the optimal response. However, Van Dyke and Charles Serhan, PhD, at Harvard Medical School have shown that when this process fails, chronic inflammation and destruction of periodontal tissues occur.⁴ A new approach to controlling periodontitis involves the potential use of proresolving molecules; bioactive lipid mediators such as lipoxins, to stop (resolve) the inflammatory response allowing healing and return to tissue homeostasis. Lipoxins are receptor agonists that control the resolution phase of acute inflammation and promote healing.^2,4 According to Van Dyke, a critical experiment demonstrated that if proresolving lipid mediators are added to the system, inflammation is resolved and healing occurs; plus bacteria like Porphyromonas gingivalis (Pg) and other periodontal pathogens are eliminated.^5,6 These experiments suggest that many of the bacteria associated with periodontal breakdown actually may be there because of the inflammation that changes the environment. In other words, the periodontal pathogens that exacerbate tissue destruction might come later in the disease process after pockets are already there. Early intervention in gingivitis should eliminate inflammatory leukocytes and prevent progression of gingivitis to periodontitis. The switch from proinflammation to proresolution is linked to expression of new genes.²

In the 1980s, research investigated the use of non-steroidal inflammatory drugs (NSAIDs) as pharmacologic agents to control inflammation in periodontitis. NSAIDs work by blocking proinflammatory pathways rather than resolving inflammation.⁷ Although NSAIDs were able to stop progression of periodontitis, unfortunately, the relatively non-specific effect of NSAIDS as COX inhibitors (all cells are affected by these enzyme inhibitors, not just inflammatory cells) resulted in side effects with long-term use that precluded application in periodontal therapy.⁸ Aspirin acts differently than other NSAIDS, and it does play an important role in resolution of inflammation. NSAIDs inactivate all COX including COX-2; aspirin turns COX-2 into a new, active enzyme, a 15-lipoxygenase. This new aspirin triggered enzyme metabolizes a new aspirin-triggered lipoxin (ATLa), which is more bioactive and possesses better proresolving properties than endogenous lipoxins. In their article about anti-inflammatory mediators, Neerudu et al. stated, “Lipoxins and aspirin-triggered lipoxins (ATLa) appear to be the first recognized members of a new class of endogenous mediators that are anti-inflammatory or serve for the ‘pro-resolution’of inflammation.”⁹

Another family of proresolving anti-inflammatory mediators, called the resolvins and protectins, are derived from dietary omega-3 polyunsaturated fatty acids rather than endogenous fatty acids (PUFA). Resolvins and protectins are derived from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the major alpha omega-3 PUFA found in fish oil.^10,11 These molecules resolve inflammation in ways that are distinct from lipoxins because they bind to distinct receptors to stop inflammation and restore tissue homeostasis.² The only cells that express receptors for resolvins are active inflammatory cells; therefore, the actions of resolvins target these cells only and have few side effects. It is interesting to note that fish oil with adequate levels of dietary omega-3 PUFAs, EPA, and DHA and low-dose aspirin have been shown to have benefits in chronic inflammatory diseases like cardiovascular diseases. In the nutriceutical world, omega-3 PUFAs are recommended for the prevention of a variety of inflammatory conditions. Interestingly, these are the only nutriceuticals that are supported by positive randomized controlled clinical trials. Perhaps the combined effect on resolution of chronic inflammation and tissue homeostasis is a related phenomenon. Experiments in animals indicate that pharmacologic control of inflammation with related new treatments (ResolvinE1) stimulates the resolution of inflammation and the restoration of bone loss in periodontitis.^5,6 Further research in humans is needed to confirm safety and effectiveness of these proresolving lipid inflammatory mediators; however, the potential for clinical application is promising.

Maria Perno Goldie, RDH, MS, president, International Federation of Dental Hygienists, discussed these new research findings as they apply to dental hygiene practice and nonsurgical periodontal therapy: “In periodontal disease, bacteria in the biofilm initiate the host response. When the inflammatory response is not resolved in the acute phase, chronic disease results. Some lipids produced by the body act as anti-inflammatory mediators. When inflammation is not resolved, the body’s response eventually leads to connective tissue and bone loss in periodontitis. These discoveries might lead to identification of a way to control chronic inflammation, not only in periodontal disease but in many systemic diseases that are related to inflammation—like heart disease and even cancers, including oral cancer. These research findings could provide information needed to develop applications for early detection and, subsequently, better management of a variety of diseases.”

Van Dyke explained that the goal of future treatments will be to control the inflammatory response. This aspect of care is equally important as removing the biofilm that initiates the disease process. Dietary omega-3 fatty acids and aspirin increase circulating proresolving lipid mediators that can resolve inflammation and restore tissue homeostasis. More potent, safe anti-inflammatory agents to prevent and treat periodontal disease and other inflammatory diseases at the molecular level will change practice. Dental hygienists potentially will be able to recommend their use in gingivitis to prevent progression of the disease or use them as adjuncts to nonsurgical or surgical periodontal therapy during the healing phase. These therapeutic agents could potentially be used for their supplemental effects against inflammation, like antibiotics are sometimes employed today, without the side effects and adverse reactions associated with overuse of antibiotics.

Dental hygienists treat inflammation every day and should learn all they can about the inflammatory process and host response because it is related to periodontal disease and potentially explains its link to systemic disease as well. Many patients see their dental hygienists two to four times a year and rarely visit their physician. A discussion of the known associations and, in the future, recommendations for new drug therapies that resolve chronic inflammation could dramatically impact our patients’ general health and well being.

Proteomics

Proteins are vital components of the human body that form many of the physiologic pathways between cells. The word “proteome” is a blend of the words “protein” and “genome” created in the mid-1990s by Marc Wilkins, an Australian geneticist.⁴ Proteome refers to all the proteins that a living organism produces, much like the genome is the entire set of genes. Proteomics is the mapping and study of those proteins, estimated at over 2 million in the human body.¹² Scientists believe that proteomics is the next logical step after genomics to better understanding an organism within its specific environment. According to the American Medical Association, “Proteomic technologies will play an important role in drug discovery, diagnostics and molecular medicine because of the link between genes, proteins and disease. As researchers study defective proteins that cause particular diseases, their findings will help develop new drugs that either alter the shape of a defective protein or mimic a missing one.”¹³

The two main research frontiers for application of proteomics in dentistry are salivary diagnostics, or oral fluid biomarkers, and proteomics of bone and enamel.³ Researchers from five universities involved in the Human Salivary Proteome Project have identified over 1,000 proteins, referred to as biomarkers, in saliva collected from the parotid and submandibular/sublingual glands, including a number of proteins found in plasma. These findings increase the likelihood that saliva-based diagnostics could eventually replace blood tests for some diseases.¹⁴ However, the ability to detect and monitor diseases through noninvasive means like salivary testing has been an elusive goal because of the complexity of saliva, including but not limited to its many proteins and their actions, functions and interactions.

While saliva is accessible and its collection is totally noninvasive, its use in clinical diagnostics has only recently been demonstrated. One team of researchers at UCLA, and others, has shown that oral fluid harbors the same composition of disease biomarkers as blood, but in smaller quantities. These scientists have developed, with support of the National Institute of Dental and Craniofacial Research, a molecular sensor that provides the basis for future development of the “Oral Fluid NanoSensor Test (OFNASET).”¹⁵ OFNASET is predicted to be a handheld and easy-to-use instrument that clinicians can use to rapidly detect complex salivary protein and nucleic acid targets. The result will be the ability to clinically detect oral cancer before oral signs and symptoms. Once this technology is developed, it will need to be further tested for safety and effectiveness and approved by the U.S. Food and Drug Administration before dental hygienists and dentists can use it for oral screenings and diagnosis.¹⁵

Proteomics and salivary diagnostics are perhaps less relevant to detection and monitoring of periodontal diseases than oral cancer because dental hygienists have the ability to clinically detect inflammation associated with gingivitis and periodontitis. Existing applications of proteomics include DNA-based saliva tests that have been marketed by OralDNA® Labs for: 1) identifying specific types of bacteria associated with periodontal disease; and 2) determining a patient’s genetic susceptibility to periodontal diseases. Saliva samples are mailed to a laboratory for analysis; therefore, chair side results are not available for immediate discussion with patients.

Future applications might include development of systems for monitoring periodontal disease activity or new drugs for the treatment of diseases, including but not limited to periodontitis. Genome and proteome information can be used to develop computer programs that detect specific proteins associated with a given disease and design targeted drug therapies.³ Sreedhar et al. explain one caveat about the future of proteomics in dental hygiene practice: “[I]ts application in the field of dentistry depends on how best oral health practitioners will incorporate this into their practice as it requires a thorough knowledge of human genetics and application of new diagnostic and therapeutic technologies.”³

References

1. National Library of Medicine. Collection development manual. National Institutes of Health. Available at: www.nlm.nih.gov/tsd/acquisitions/cdm/subjects64.html.

2. Van Dyke TE. Proresolving lipid mediators: potential for prevention and treatment of periodontitis. J Clin Periodontol. 2011; 38 (Suppl. 11): 119-125. doi: 10.1111/j.1600-051X.2010.01662.x.

3. Sreedhar A, Shobha P, Sapna N, Santhosh K. Inflammatory mediators—molecules that are released by immune cells during times when harmful agents invade our body. J Dent Sci Res. n.d., 2(2):87-90. Available at: Accessed Dec. 15, 2011.

4. Van Dyke TE, Serhan CN. Resolution of inflammation: a new paradigm for the pathogenesis of periodontal diseases. J Dent Res. 2003; 82: 82-90.

5. Hasturk H, Kantarci A, Goguet-Surmenian E, et al. Resolvin E1 regulates inflammation at the cellular and tissue level and restores tissue homeostasis in vivo. J Immunol. 2007; 179: 7021-9.

6. Hasturk H, Kantarci A, Ohira T, et al. RvE1 protects from local inflammation and osteoclastmediated bone destruction in periodontitis. Faseb J. 2006; 20:401-3.

7. Serhan CN, Brain SD, Buckley CD, et al. Resolution of inflammation: state of the art, definitions and terms. Faseb J. 2007; 21: 325-32.

8. Williams RC, Jeffcoat MK, Howell TH, et al. Topical flurbiprofen treatment of periodontitis in beagles. J Periodont Res 1988; 23: 166-9.

9. Neerudu M, Rajababu, Reddy H, Koppolu P. Anti-inflammatory mediators. Indian J Dent Advancements. 2010; 2(2) April-June.

10. Van Dyke TE. Control of inflammation and periodontitis. Periodont 2000 2007; 45: 158-66.

11. Serhan CN, Chiang N, Van Dyke TE. Resolving inflammation: dual antiinflammatory and pro-resolution lipid mediators. Nat Rev Immunol. 2008; 8: 349–61.

12. Wilkins MR, Pasquali C, Appel RD, et al. From proteins to proteomes: large scale protein identification by two-dimensional electrophoresis and amino acid analysis. Biotechnology. 1996; 14(1): 61-5.

13. American Medical Association. Current topics. proteomics. Available at: www.ama-assn.org/ama/pub/physician-resources/medical-science/geneticsmolecular-medicine/current-topics/proteomics.page. Accessed Dec. 5, 2011.

14. Fong T. Researchers publish ‘most comprehensive’ map of salivary proteome; dxs on horizon? Proteomonitor, The Global Newsweekly of Proteomics Technology. April 3, 2008. Available at: www.genomeweb.com/proteomics/researchers-publish-%E2%80%98mostcomprehensive%E2%80%99-map-salivary-proteome-dxs-horizon-0. Accessed Dec. 23, 2011.

15. UCLA Human Salivary Proteome Project Website. Available at: hspp.dent. ucla.edu/OFNASET.htm. Accessed Dec. 22, 2011.

Author

Denise Bowen, RDH, MS
Professor Emeritus
Idaho State University
Pocatello, Idaho