DOI:10.32604/biocell.2022.018031
| BIOCELL DOI:10.32604/biocell.2022.018031 | |
| Viewpoint |
Periodontal research contributions to basic sciences: From cell communication and host-parasite interactions to inflammation and bone biology
1Federal University of Rio de Janeiro - UFRJ, Rio de Janeiro, 21941-617, Brazil
2São Paulo State University - UNESP, Araraquara, 14801-930, Brazil
3Federal University of Parana - UFPR, Curitiba, 80210-170, Brazil
*Address correspondence to: Rafael Scaf de Molon, rafael.molon@odonto.ufrj.br
Received: 02 June 2021; Accepted: 13 August 2021
Abstract: The periodontium comprises all structures surrounding the teeth, including gingiva, root cementum, periodontal ligament and alveolar bone. Those tissues aim to protect and support the teeth and are challenged by a residing microbiota that leads to subclinical inflammation even in physiological conditions. Periodontitis, a prevalent multicausal inflammatory and destructive disease, develops as a result from complex host-parasite interactions. This unique physiologic and pathologic scenario enables the development of research methods which allows conclusions beyond the simple understanding of periodontal homeostasis. The aim of this viewpoint was to explore potential contributions of periodontal research to a wide array of basic science specialties, such as cell and molecular biology, microbiology, immunology, endocrinology, rheumatology, among others.
Keywords: Alveolar bone; Bone; Periodontal disease; Rheumatoid arthritis
The tooth-surrounding structures (a.k.a., periodontium) are comprised of gingiva, root cementum, periodontal ligament and alveolar bone. Gingiva is formed of diverse–in location and features-epithelial layers (i.e., sulcular, junctional and oral epithelium) on top of an underlying connective tissue. Fibroblasts, epithelial cells, cementoblasts, cementocytes, osteoblasts, osteoclasts and osteocytes are some of the tissue-specific cell components of this great complex structure, which also includes blood vessels, nerves, and extracellular matrix (Nanci and Bosshardt, 2006).
Periodontal literature greatly contributes to dental research, with dedicated journals being ranked #1, #2 and #3 in Dentistry, Oral Surgery and Medicine Category of Journal Citations Report 2020. Over the recent years, the core periodontal journals have increased their impact factors approximately 50–100%, suggesting their contributions for both oral health care and medicine (Ahmad and Slots, 2021). Moreover, a recent study showed that from the 300 most cited articles published in periodontology, basic sciences including microbiology comprised more than 50% of the included articles (Faggion et al., 2017). Therefore, not only periodontal knowledge may benefit from basic sciences development, but the opposite is also true.
The aim of this viewpoint was to explore potential contributions of periodontal research to a wide array of basic science specialties, such as cell and molecular biology, microbiology, immunology, endocrinology, rheumatology, among others.
Different cell types act together to dictate the homeostasis of periodontal tissues. Innate and adaptive immune cells contribute through the release of their molecules trying to maintain homeostasis in periodontal tissues, so the host immune response plays a pivotal role in protect against periodontal pathogens (Becerra-Ruiz et al., 2021). Understanding specific cell response in physiological and ‘challenged’ conditions, as well as cell response to different potential treatments, has been the focus of several investigations. Also, co-culture has been used as a model to better characterize interaction between cell types in this scenario (Bedran et al., 2014; Loomer et al., 1998). Additionally, the periodontal ligament space harbors mesenchymal stem cells that can potentially regenerate biological structures and deserves special attention (Liu et al., 2019).
However, homeostasis of the periodontal tissues is frequently disturbed, since microbial accumulation on the tooth and gingival crevice occurs right after every attempt for plaque removal. As a consequence, subclinical inflammation characterized by histological neutrophil infiltrate, with some macrophages and very few plasma cells can be frequently observed in physiological conditions (Hajishengallis and Korostoff, 2017). In this scenario, potential periodontopathogens have been characterized and studied, such as Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Tannerella forsythia, Prevotella intermedia and Treponema denticola. Some of those microorganisms have also been involved in other systemic diseases. For example, P. gingivalis and A. actinomycetemcomitans have been detected in coronary atheromatous plaque, suggesting systemic dissemination of oral pathogens (Joshi et al., 2021). Additionally, P. gingivalis and A. actinomycetemcomitans have also been linked to the pathogenesis of rheumatoid arthritis (RA) throughout different mechanisms, as briefly described down below (de Molon et al., 2019a). Hence, observations from host-parasite interactions in the periodontium may serve as basis for useful models to characterize other microbial-associated systemic diseases as well.
Periodontal disease (PD) is a complex, high prevalent and multicausal chronic inflammatory disease associated with a dysbiotic biofilm and characterized by loss of gingival tissue, periodontal ligament, cement and alveolar bone (Papapanou et al., 2018). It is considered a main cause of tooth loss in the adult population. Severe PD is the sixth most prevalent disease worldwide, with an overall prevalence of 11.2% and 734 million people affected (Richards, 2014). Various animal models have been used to mimic the observed features of periodontitis such as inflammatory infiltrate and bone loss around teeth. The development of PD through different animal models can be separated into different phases comprising the development of biofilm, invasion of periodontal pathogenic bacteria and their proinflammatory products, and the induction of a destructive host response (Marchesan et al., 2018). Although no single animal model can replicate the complexity of PD (Hajishengallis et al., 2015), distinctive phases of the disease can be addressed by three main animal models of PD, which include ligature placement, bacterial lipopolysaccharide (LPS) injections, and bacterial challenge in rodents. Briefly, the ligature-induced bone loss is one of the most utilized experimental PD model (da Ponte Leguizamon et al., 2021). The rationale behind the ligature model is based on the accumulation of bacteria around the thread (silk or nylon) to sustain the inflammation and bone loss. It has been considered as an acute model of periodontal tissue breakdown resulting in two distinct phases: Acute (0–14 days), characterized by inflammation, increased gene expression of IL-6, IL-1β, TNF-α, RANKL, and OPG, and rapid alveolar bone destruction; and chronic (14–21 days) with no significant progression of bone loss (de Molon et al., 2018). The major drawback of this model is the mechanical trauma caused during the ligature placement, especially in small rodents (de Molon et al., 2013), which demands very high level of technical skills. Furthermore, the bacterial lipopolysaccharide (LPS) model is also highly employed in periodontal research due to the predictability of the bone resorption caused by the continuous injection of LPS into the gingival tissue (de Molon et al., 2014; Graves et al., 2008; Graves et al., 2012). Finally, the oral inoculation model (oral gavage) with live bacteria (or consortium of bacterial species) is perhaps the model that best represents the PD in humans (de Molon et al., 2013). The rationale behind it is to allow the adherence and colonization of the exogenous bacteria to grow into the animal mouth leading to an increase in pro-inflammatory mediators, inflammatory process and bone destruction. However, the disadvantage of this model is the increased time to consistently develop alveolar bone loss once bacteria need to colonize, grow, and then cause the disease (de Molon et al., 2016).
It is noteworthy to mention the humanized mice models, which have been described as immuno-deficient mice engrafted with human hematopoietic cells and/or tissues capable of reconstituting a functional immune system. These models allow the study of human biological processes and affections. There are 3 main humanized mice models: the human stem cells (hu-HSC) model, the human peripheral blood lymphocytes (hu-PBL) model, and the human bone marrow/fetal liver/thymus (BLT) model. A complete description of the humanized mice models can be found in a review article (Rojas et al., 2021). It is important to bear in mind that all experimental models of PD have their own limitation that are inherent of the model, and no one single model is able to replicate all aspects of human periodontitis.
Those models, apart from studying periodontal diseases, are also useful for 1) understanding systemic responses to low-grade inflammation; 2) characterizing bone biology and osteoimmunology in pathological scenarios; and 3) understanding the inflammatory and immunological processes (Cavagni et al., 2016). For example, the role of sex hormones on periodontal health, inflammation and bone loss, and periodontal healing has been described and those findings can be extrapolated to different inflammatory diseases as well (Steffens et al., 2015; Steffens et al., 2018). Moreover, studies using experimental PD models have clarified the pivotal role of bacteria in starting the host inflammatory response that leads to periodontal tissue breakdown and have identified key mediators (IL-1, TNF, prostaglandins, complement, RANKL) that induce inflammatory breakdown (Hajishengallis et al., 2015) and might affect other systemic diseases. In this context, it is well documented that diabetes mellitus increase the risk and severity of PD (Chapple et al., 2013). PD models have recognized a mechanistic basis for this association through the increased formation of advanced glycation end products.
Also, new treatment modalities that benefit periodontal diseases can be understood as potential treatments for other inflammatory conditions. For instance, specialized proresolvin mediators (SPMs) are a novel family of oxylipids mediators including resolvins, maresins, lipoxins and protectins derived from omega-3 polyunsaturated fatty acid (PUFA), which regulate the inflammatory process without immunosuppression (Balta et al., 2021). The SPMs function in the termination of inflammation by activating specific mechanisms to restore tissue homeostasis (Serhan, 2014; Serhan et al., 2008). Briefly, they selectively inhibit leukocyte recruitment, activate macrophage phagocytosis of microorganisms, stimulate infiltration of monocytes, and stimulate expression of molecules involved in antimicrobial defense (de Molon et al., 2019b). Such SPMs promote tissue repair, elimination of bacteria, increase the host defense, and can impact the responses of adaptive immune cells (Mizraji et al., 2018). Resolvins have been suggested as a potential treatment targeting the inflammatory process in periodontal diseases with promising results that could extrapolate its benefits from the local periodontal setting (Hamilton et al., 2017). In this regard, Hasturk et al. demonstrated that topical application RvE1 was able to prevent initiation and progression of experimental PD, and even induce the regeneration of periodontal tissues (alveolar bone, periodontal ligament and cement) in a rabbit model of ligature-induced bone loss (Hasturk et al., 2007; Hasturk et al., 2006). RvE1 downregulated the progression of PD by decreasing proinflammatory mediators and reducing inflammatory bone loss. Studies investigating the effects of different SPMs, such as resolvin E1, maresins, and resolvin E2 treatment on other diseases have been described in the recent literature throughout different mechanisms. Most of them showed beneficial effects of SPMs on neuro-inflammation (Derada Troletti et al., 2021), tuberculosis (Hayford et al., 2021), wound healing, diabetes, (Shofler et al., 2021), and chronic inflammation (Lamon-Fava et al., 2021), just to cite a few.
Moreover, periodontitis has been epidemiologically associated with several other noncommunicable diseases (NCDs), such as diabetes mellitus, cardiovascular diseases, obesity and RA (Beck et al., 2019; Hajishengallis and Chavakis, 2021; Marcantonio et al., 2021). Recent data on interventional studies indicates that PD treatment ameliorates surrogate-markers of inflammation-driven disorders (D’Aiuto et al., 2018; Teles and Wang, 2011; Moura et al., 2021). Potential causal mechanisms involve periodontal-related microbial (or their byproducts) and inflammatory pathways that contribute to the development of the systemic conditions (Winning et al., 2015). For instance, the most described biologic plausibility linking PD and other systemic conditions rely on the translocation of microorganisms and/or their products through the ulcerated epithelium of the periodontal pocket to the bloodstream. This might lead to systemic alteration in consequence to the increased immunological response of the host to the virulent factors of the bacterial species, as shown in Fig. 1. On the other hand, it is also possible that the observed associations derive from shared risk factors to NCDs, such as smoking, genetic background, gut microbiota, physical inactivity, unhealthy diet and harmful use of alcohol (Tonetti et al., 2017).
Figure 1: An overview of periodontal disease characteristics and how it affects other systemic diseases. PD is initiated by a dysbiotic biofilm in intimate contact with the gingival tissue. In a homeostatic situation (upper left circle) there is predominance of fibroblast and few inflammatory cells (neutrophils, macrophages, and T cells) in the connective tissue. With the progression of PD (represented by the circle in the upper center) there is predominance of B cells (plasma cells) and T cells due to the activation of the host adaptive immune response trying to eliminate the bacteria antigens. The adaptive host response is responsible for the majority of tissue destruction observed during the PD progression, which leads to the activation of osteoclasts, the cells accountable for the resorption of the alveolar bone, leading to the clinical signs of periodontitis (represented by the rectangle). One of the biologically plausible mechanisms linking PD to other non-communicable diseases rely on the translocation of bacteria from the ulcerated epithelium to the blood stream (represented by the central and inferior circles), which can reach other tissues from the host, such as heart, lung, intestine, pancreas, and joints) and is represented in Fig. 1 by the human body in the right of the panel.
Of importance, RA has been linked to PD in several translational and clinical studies (de Molon et al., 2019a; de Aquino et al., 2017; de Aquino et al., 2014). Despite its common pathological features between RA and PD (increased infiltration of inflammatory and immune cells, increased expression of pro-inflammatory mediators and degrading enzymes, and osteoclast activation), P. gingivalis and A. actinomycetemcomitans have also been associated to the RA pathogenesis. P. gingivalis is the only known microorganism that is able to express the peptidylarginine deiminase (PAD), an enzyme that mediate the post-translational modification of the amino acid arginine into citrulline, a process called citrullination (Mangat et al., 2010). Increased formation of citrullinated proteins can act as autoantigens, leading to the production of auto-antibodies favoring the RA pathogenesis. Thus, resulting in the generation of an immune response to citrullinated self-antigens (Rosenstein et al., 2004). Furthermore, A. actinomycetemcomitans leads to the hypercitrullination of neutrophils and, as a result, there is activation of citrulline enzymes, which are also involved in the breakdown of the immune tolerance to the host molecules (Konig et al., 2016). PD has also been linked with other rheumatic diseases such as, psoriatic arthritis (Ustun et al., 2013; Sezer et al., 2016), ankylosing spondylitis (Enginar et al., 2021; Pandey et al., 2020), systemic lupus erythematosus (Bolstad et al., 2021; Sojod et al., 2021), and osteoarthritis (Kim et al., 2020).
Taken together, periodontal research can contribute to the understanding of pathogenic mechanisms of several inflammatory diseases.
There is growing body of evidence demonstrating that PD negatively impacts systemic health and several inflammatory conditions, such as diabetes, cardiovascular diseases, RA, pregnancy outcomes, pulmonary diseases, and others, through different mechanisms (Hajishengallis and Chavakis, 2021). On the other hand, clinical, interventional and experimental studies suggest that different NCDs also affect PD initiation and progression. It is important to bear in mind that the development of research methods of experimental periodontitis might contribute significantly to study potential biological mechanisms of a wide range of NCDs and their association with PD. Furthermore, basic science can also contribute to the understanding of PD pathogenesis and its effects on systemic conditions. Future translational research should target the mechanism, understanding the potential link among periodontitis and other inflammatory conditions.
Emerging evidence on the field of mechanobiology have been described recently (Jang et al., 2018; Dieterle et al., 2021; Gauthier et al., 2021). The periodontium, made of tissues of different natures, shows a complicated biomechanical environment. It is known that the activity of the different cell types are greatly influenced by this biomechanical environment, that is studied in the field of mechanobiology. Investigating this mechanical environment to understand how the mechanical cues are transmitted to the osteocytes of the alveolar bone, to the cementoblasts of the cementum, or to the fibroblasts of the periodontal ligament might be of great interest for those who are interested in general cell mechanobiology. More specifically, the periodontal ligament being a soft tissue, understanding what occurs in terms of biomechanics, at the interface between the ligament and the bone is relevant to understanding how bone cells respond to a very specific biomechanical cue. The issue of interface between bone and other type of tissues, such as other ligaments or cartilage, is still a great challenge. Indeed, understanding periodontium biomechanics and mechanobiology can contribute to better understanding other joints’ biomechanics and mechanobiology and osteoarticular pathologies.
Availability of Data Material: Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.
Author Contribution: The authors confirm contribution to the paper as follows: study conception and design: RSM, EDA, JAC, and JPS; draft manuscript preparation: RSM, EDA, JAC, and JPS. All authors reviewed the article text and approved the final version of the manuscript.
Funding Statement: de Molon RS was supported by grant provided by CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior) Grant # 88887.583248/2020-00.
Conflicts of Interest: The authors declare that they have no conflicts of interest to report regarding the present study.
Ahmad P, Slots J (2021). A bibliometric analysis of periodontology. Periodontology 2000 85: 237–240. DOI 10.1111/prd.12376. [Google Scholar] [CrossRef]
Balta MG, Papathanasiou E, Blix IJ, Van Dyke TE (2021). Host modulation and treatment of periodontal disease. Journal of Dental Research 100(8798–809. DOI 10.1177/0022034521995157 22034521995157. [Google Scholar] [CrossRef]
Becerra-Ruiz JS, Guerrero-Velazquez C, Martinez-Esquivias F, Martinez-Perez LA, Guzman-Flores JM (2021). Innate and adaptive immunity of periodontal disease. From etiology to alveolar bone loss. Oral Disease. [Google Scholar]
Beck JD, Papapanou PN, Philips KH, Offenbacher S (2019). Periodontal medicine: 100 years of progress. Journal of Dental Research 98: 1053–1062. DOI 10.1177/0022034519846113. [Google Scholar] [CrossRef]
Bedran TB, Mayer MP, Spolidorio DP, Grenier D (2014). Synergistic anti-inflammatory activity of the antimicrobial peptides human beta-defensin-3 (hBD-3) and cathelicidin (LL-37) in a three-dimensional co-culture model of gingival epithelial cells and fibroblasts. PLoS One 9: e106766. DOI 10.1371/journal.pone.0106766. [Google Scholar] [CrossRef]
Bolstad AI, Sehjpal P, Lie SA, Fevang BS (2021). Periodontitis in patients with systemic lupus erythematosus: A nation-wide study of 1990 patients. Journal of Periodontology 11: 38. DOI 10.1002/JPER.21-0181. [Google Scholar] [CrossRef]
Cavagni J, de Macedo IC, Gaio EJ, Souza A, de Molon RS et al. (2016). Obesity and hyperlipidemia modulate alveolar bone loss in wistar rats. Journal of Periodontology 87: e9–e17. DOI 10.1902/jop.2015.150330. [Google Scholar] [CrossRef]
Chapple IL, Genco R, on behalf of working group 2 of the joint EFP/AAP workshop (2013). Diabetes and periodontal diseases: Consensus report of the Joint EFP/AAP Workshop on Periodontitis and Systemic Diseases. Journal of Periodontology 84: S106–S112. DOI 10.1902/jop.2013.1340011. [Google Scholar] [CrossRef]
D’Aiuto F, Gkranias N, Bhowruth D, Khan T, Orlandi M et al. (2018). Systemic effects of periodontitis treatment in patients with type 2 diabetes: A 12 month, single-centre, investigator-masked, randomised trial. Lancet Diabetes and Endocrinology 6: 954–965. DOI 10.1016/S2213-8587(18)30038-X. [Google Scholar] [CrossRef]
da Ponte Leguizamon N, de Molon RS, Coletto-Nunes G, Nogueira AVB, Rocha SV et al. (2021). Phytocystatin csinCPI-2 reduces osteoclastogenesis and alveolar bone loss. Journal of Dental Research 1–10. DOI 10.1177/00220345211027811. [Google Scholar] [CrossRef]
de Aquino SG, Abdollahi-Roodsaz S, Koenders MI, van de Loo FA, Pruijn GJ et al. (2014). Periodontal pathogens directly promote autoimmune experimental arthritis by inducing a TLR2- and IL-1-driven Th17 response. Journal of Immunology 192: 4103–4111. DOI 10.4049/jimmunol.1301970. [Google Scholar] [CrossRef]
de Aquino SG, Talbot J, Sonego F, Turato WM, Grespan R et al. (2017). The aggravation of arthritis by periodontitis is dependent of IL-17 receptor A activation. Journal of Clinical Periodontology 44: 881–891. DOI 10.1111/jcpe.12743. [Google Scholar] [CrossRef]
de Molon RS, de Avila ED, Boas Nogueira AV, Chaves de Souza JA, Avila-Campos MJ et al. (2014). Evaluation of the host response in various models of induced periodontal disease in mice. Journal of Periodontology 85: 465–477. DOI 10.1902/jop.2013.130225. [Google Scholar] [CrossRef]
de Molon RS, de Avila ED, Cirelli JA (2013). Host responses induced by different animal models of periodontal disease: A literature review. Journal of Investigative and Clinical Dentistry 4: 211–218. DOI 10.1111/jicd.12018. [Google Scholar] [CrossRef]
de Molon RS, Mascarenhas VI, de Avila ED, Finoti LS, Toffoli GB et al. (2016). Long-term evaluation of oral gavage with periodontopathogens or ligature induction of experimental periodontal disease in mice. Clinical Oral Investigations 20: 1203–1216. DOI 10.1007/s00784-015-1607-0. [Google Scholar] [CrossRef]
de Molon RS, Park CH, Jin Q, Sugai J, Cirelli JA (2018). Characterization of ligature-induced experimental periodontitis. Microscopy Research and Technique 81: 1412–1421. DOI 10.1002/jemt.23101. [Google Scholar] [CrossRef]
de Molon RS, Rossa CJr., Thurlings RM, Cirelli JA, Koenders MI (2019a). Linkage of periodontitis and rheumatoid arthritis: Current evidence and potential biological interactions. International Journal of Molecular Sciences 20: 4541. DOI 10.3390/ijms20184541. [Google Scholar] [CrossRef]
de Molon RS, Thurlings RM, Walgreen B, Helsen MM, van der Kraan PM et al. (2019b). Systemic Resolvin E1 (RvE1) Treatment does not ameliorate the severity of Collagen-Induced Arthritis (CIA) in Mice: A randomized, prospective, and controlled proof of concept study. Mediators of Inflammation 2019: 1–14. DOI 10.1155/2019/5689465. [Google Scholar] [CrossRef]
Derada Troletti C, Enzmann G, Chiurchiu V, Kamermans A, Tietz SM et al. (2021). Pro-resolving lipid mediator lipoxin A4 attenuates neuro-inflammation by modulating T cell responses and modifies the spinal cord lipidome. Cell Reports 35: 109201. DOI 10.1016/j.celrep.2021.109201. [Google Scholar] [CrossRef]
Dieterle MP, Husari A, Steinberg T, Wang X, Ramminger I et al. (2021). Role of mechanotransduction in periodontal homeostasis and disease. Journal of Dental Research 100(111210–1219. DOI 10.1177/00220345211007855. [Google Scholar] [CrossRef]
Enginar AU, Daltaban O, Kacar C, Tuncer T (2021). Relationship between periodontal status and disease activity in patients with ankylosing spondylitis. Reumatologia/Rheumatology 59: 35–40. DOI 10.5114/reum.2021.103643. [Google Scholar] [CrossRef]
Faggion CMJr., Malaga L, Monje A, Trescher AL, Listl S et al. (2017). The 300 most cited articles published in periodontology. Clinical Oral Investigations 21: 2021–2028. DOI 10.1007/s00784-016-1990-1. [Google Scholar] [CrossRef]
Gauthier R, Jeannin C, Attik N, Trunfio-Sfarghiu AM, Gritsch K et al. (2021). Tissue engineering for periodontal ligament regeneration: Biomechanical specifications. Journal of Biomechanical Engeneering 143(3030801. DOI 10.1115/1.4048810. [Google Scholar] [CrossRef]
Graves DT, Fine D, Teng YT, van Dyke TE, Hajishengallis G (2008). The use of rodent models to investigate host-bacteria interactions related to periodontal diseases. Journal of Clinical Periodontology 35: 89–105. DOI 10.1111/j.1600-051X.2007.01172.x. [Google Scholar] [CrossRef]
Graves DT, Kang J, Andriankaja O, Wada K, Rossa CJr (2012). Animal models to study host-bacteria interactions involved in periodontitis. Frontiers of Oral Biology 15: 117–132. DOI 10.1159/000329675. [Google Scholar] [CrossRef]
Hajishengallis G, Chavakis T (2021). Local and systemic mechanisms linking periodontal disease and inflammatory comorbidities. Nature Reviews Immunology 21: 426–440. DOI 10.1038/s41577-020-00488-6. [Google Scholar] [CrossRef]
Hajishengallis G, Korostoff JM (2017). Revisiting the Page & Schroeder model: The good, the bad and the unknowns in the periodontal host response 40 years later. Periodontology 75: 116–151. DOI 10.1111/prd.12181. [Google Scholar] [CrossRef]
Hajishengallis G, Lamont RJ, Graves DT (2015). The enduring importance of animal models in understanding periodontal disease. Virulence 6: 229–235. DOI 10.4161/21505594.2014.990806. [Google Scholar] [CrossRef]
Hamilton JA, Hasturk H, Kantarci A, Serhan CN, van Dyke T (2017). Atherosclerosis, periodontal disease, and treatment with resolvins. Current Atherosclerosis Reports 19: e21. DOI 10.1007/s11883-017-0696-4. [Google Scholar] [CrossRef]
Hasturk H, Kantarci A, Goguet-Surmenian E, Blackwood A, Andry C et al. (2007). Resolvin E1 regulates inflammation at the cellular and tissue level and restores tissue homeostasis in vivo. Journal of Immunology 179: 7021–7029. DOI 10.4049/jimmunol.179.10.7021. [Google Scholar] [CrossRef]
Hasturk H, Kantarci A, Ohira T, Arita M, Ebrahimi N, Chiang N, Petasis NA, Levy BD, Serhan CN, van Dyke TE (2006). RvE1 protects from local inflammation and osteoclast- mediated bone destruction in periodontitis. FASEB Journal 20: 401–403. DOI 10.1096/fj.05-4724fje. [Google Scholar] [CrossRef]
Hayford FEA, Ozturk M, Dolman RC, Blaauw R, Nienaber A et al. (2021). Longer-term omega-3 LCPUFA more effective adjunct therapy for tuberculosis Than ibuprofen in a C3HeB/FeJ tuberculosis mouse model. Frontiers in Immunology 12: 475. [Google Scholar]
Jang AT, Chen L, Shimotake AR, Landis W, Altoe V et al. (2018). A force on the crown and tug of war in the periodontal complex. Journal of Dental Research 97: 241–250. DOI 10.1177/0022034517744556. [Google Scholar] [CrossRef]
Joshi C, Bapat R, Anderson W, Dawson D, Hijazi K et al. (2021). Detection of periodontal microorganisms in coronary atheromatous plaque specimens of myocardial infarction patients: A systematic review and meta-analysis. Trends in Cardiovascular Medicine 31: 69–82. DOI 10.1016/j.tcm.2019.12.005. [Google Scholar] [CrossRef]
Kim JW, Chung MK, Lee J, Kwok SK, Kim WU et al. (2020). Association of periodontitis with radiographic knee osteoarthritis. Journal of Periodontology 91: 369–376. DOI 10.1002/JPER.19-0068. [Google Scholar] [CrossRef]
Konig MF, Abusleme L, Reinholdt J, Palmer RJ, Teles RP et al. (2016). Aggregatibacter actinomycetemcomitans-induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis. Science and Translational Medicine 8: 369ra176. DOI 10.1126/scitranslmed.aaj1921. [Google Scholar] [CrossRef]
Lamon-Fava S, So J, Mischoulon D, Ziegler TR, Dunlop BW et al. (2021). Dose- and time-dependent increase in circulating anti-inflammatory and pro-resolving lipid mediators following eicosapentaenoic acid supplementation in patients with major depressive disorder and chronic inflammation. Prostaglandins, Leukotriene Essential Fatty Acids 164: 102219. DOI 10.1016/j.plefa.2020.102219. [Google Scholar] [CrossRef]
Liu J, Ruan J, Weir MD, Ren K, Schneider A et al. (2019). Periodontal bone-ligament-cementum regeneration via scaffolds and stem cells. Cells 8: 537. DOI 10.3390/cells8060537. [Google Scholar] [CrossRef]
Loomer PM, Ellen RP, Tenenbaum HC (1998). Effects of Porphyromonas gingivalis 2561 extracts on osteogenic and osteoclastic cell function in co-culture. Journal of Periodontology 69: 1263–1270. DOI 10.1902/jop.1998.69.11.1263. [Google Scholar] [CrossRef]
Mangat P, Wegner N, Venables PJ, Potempa J (2010). Bacterial and human peptidylarginine deiminases: Targets for inhibiting the autoimmune response in rheumatoid arthritis? Arthritis Research & Therapy 12: 209. DOI 10.1186/ar3000. [Google Scholar] [CrossRef]
Marcantonio CC, Nogueira AVB, Leguizamon NDP, de Molon RS, Lopes MES et al. (2021). Effects of obesity on periodontal tissue remodeling during orthodontic movement. American Journal of Orthodontics and Dentofacial Orthopedics 159: 480–490. DOI 10.1016/j.ajodo.2019.12.025. [Google Scholar] [CrossRef]
Marchesan J, Girnary MS, Jing L, Miao MZ, Zhang S et al. (2018). An experimental murine model to study periodontitis. Nature Protocols 13: 2247–2267. DOI 10.1038/s41596-018-0035-4. [Google Scholar] [CrossRef]
Mizraji G, Heyman O, van Dyke TE, Wilensky A (2018). Resolvin D2 restrains Th1 immunity and prevents alveolar bone loss in murine periodontitis. Frontiers in Immunology 9: 1501. DOI 10.3389/fimmu.2018.00785. [Google Scholar] [CrossRef]
Moura MF, Silva TA, Cota LOM, Oliveira SR, Cunha FQ et al. (2021). Nonsurgical periodontal therapy decreases the severity of rheumatoid arthritis and the plasmatic and salivary levels of RANKL and Survivin: A short-term clinical study. Clinical Oral Investigations 15: 30. [Google Scholar]
Nanci A, Bosshardt DD (2006). Structure of periodontal tissues in health and disease. Periodontology 2000 40: 11–28. DOI 10.1111/j.1600-0757.2005.00141.x. [Google Scholar] [CrossRef]
Pandey A, Rajak R, Pandey M (2020). Periodontal diseases and its association with disease activity in ankylosing spondylitis/SpA: A systematic review. European Journal of Rheumatology. 1: 1–12 DOI 10.5152/eurjrheum.2020.20177 online ahead of print. [Google Scholar] [CrossRef]
Papapanou PN, Sanz M, Buduneli N, Dietrich T, Feres M et al. (2018). Periodontitis: Consensus report of workgroup 2 of the 2017 World Workshop on the Classification of Periodontal and Peri-Implant Diseases and Conditions. Journal of Periodontology Suppl 1: S173–S182. [Google Scholar]
Richards D (2014). Review finds that severe periodontitis affects 11% of the world population. Evidence Based Dentistry 15: 70–71. [Google Scholar]
Rojas C, Garcıa MP, Polanco AF, Gonzalez-Osuna L, Sierra-Cristancho A et al. (2021). Humanized mouse models for the study of periodontitis: An opportunity to elucidate unresolved aspects of its immunopathogenesis and analyze new immunotherapeutic strategies. Frontiers in Immunology, 12: 663328. DOI 10.3389/fimmu.2021.663328. [Google Scholar] [CrossRef]
Rosenstein ED, Greenwald RA, Kushner LJ, Weissmann G (2004). Hypothesis: The humoral immune response to oral bacteria provides a stimulus for the development of rheumatoid arthritis. Inflammation 28: 311–318. [Google Scholar]
Serhan CN (2014). Pro-resolving lipid mediators are leads for resolution physiology. Nature 510: 92–101. [Google Scholar]
Serhan CN, Chiang N, van Dyke TE (2008). Resolving inflammation: Dual anti-inflammatory and pro-resolution lipid mediators. Nature Reviews Immunology 8: 349–361. [Google Scholar]
Sezer U, Senyurt SZ, Gundogar H, Erciyas K, Ustun K et al. (2016). Effect of chronic periodontitis on oxidative status in patients with psoriasis and psoriatic arthritis. Journal of Periodontology 87: 557–565. DOI 10.1902/jop.2015.150337. [Google Scholar] [CrossRef]
Shofler D, Rai V, Mansager S, Cramer K, Agrawal DK (2021). Impact of resolvin mediators in the immunopathology of diabetes and wound healing. Expert Reviews Clinical Immunology, 17(6681–690. DOI 10.1080/1744666X.2021.1912598. [Google Scholar] [CrossRef]
Sojod B, Pidorodeski Nagano C, Garcia Lopez GM, Zalcberg A, Dridi SM et al. (2021). Systemic lupus erythematosus and periodontal disease: A complex clinical and biological interplay. Journal of Clinical Medicine, 10(91957. DOI 10.3390/jcm10091957. [Google Scholar] [CrossRef]
Steffens JP, Coimbra LS, Rossa CJr., Kantarci A, van Dyke TE et al. (2015). Androgen receptors and experimental bone loss - an in vivo and in vitro study. Bone 81: 683–690. DOI 10.1016/j.bone.2015.10.001. [Google Scholar] [CrossRef]
Steffens JP, Santana LCL, Pitombo JCP, Ribeiro DO, Albaricci MCC et al. (2018). The role of androgens on periodontal repair in female rats. Journal of Periodontology 89: 486–495. DOI 10.1002/JPER.17-0435. [Google Scholar] [CrossRef]
Teles R, Wang CY (2011). Mechanisms involved in the association between peridontal diseases and cardiovascular disease. Oral Diseases 17: 450–461. DOI 10.1111/j.1601-0825.2010.01784.x. [Google Scholar] [CrossRef]
Tonetti MS, Jepsen S, Jin L, Otomo-Corgel J (2017). Impact of the global burden of periodontal diseases on health, nutrition and wellbeing of mankind: A call for global action. Journal of Clinical Periodontology 44: 456–462. DOI 10.1111/jcpe.12732. [Google Scholar] [CrossRef]
Ustun K, Sezer U, Kisacik B, Senyurt SZ, Ozdemir EC et al. (2013). Periodontal disease in patients with psoriatic arthritis. Inflammation 36: 665–669. DOI 10.1007/s10753-012-9590-y. [Google Scholar] [CrossRef]
Winning L, Patterson CC, Cullen KM, Stevenson KA, Lundy FT et al. (2015). The association between subgingival periodontal pathogens and systemic inflammation. Journal of Clinical Periodontology 42: 799–806. DOI 10.1111/jcpe.12450. [Google Scholar] [CrossRef]
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