|Year : 2016 | Volume
| Issue : 1 | Page : 14-26
Delineating periodontal research: Climb is worth the view
Harpreet Singh Grover1, Veenu Madaan Hans1, Mayank Hans2
1 Department of Periodontology, Shree Guru Gobind Singh Tricentenary (SGT) University, Gurgaon, Haryana, India
2 Department of Dentistry, ESIC Medical College and Hospital, Faridabad, Haryana, India
|Date of Web Publication||12-Feb-2016|
Dr. Veenu Madaan Hans
Department of Periodontology, Faculty of Dental Sciences, Shree Guru Gobind Singh Tricentenary (SGT) University, Gurgaon, Haryana, Delhi-NCR
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Research in field of periodontology has seen an expansion in the past few decades, which has led to a greater understanding of the disease. Recent research has changed how we think about the etiology and pathogenesis of periodontal disease. Although bacteria are essential for causing periodontitis, the reaction of the host's immune system is accountable for the majority of the destruction found in periodontal disease. Novel risk factors are being identified and it has been established that environmental and genetic factors may alter the course of periodontal disease. Research in the past decades has indicated that oral health influences overall health and the course of some systemic diseases. Recently, the focus has shifted to an evidence-based approach, which connects the laboratory and clinical data to therapeutic decision-making. Thus, the ultimate aim of all the ongoing research is to prevent the occurrence of disease, control the ongoing disease, and treat the damage already done.
Keywords: Etiology, pathogenesis, periodontal medicine, periodontal research, periodontitis
|How to cite this article:|
Grover HS, Hans VM, Hans M. Delineating periodontal research: Climb is worth the view. J Int Clin Dent Res Organ 2016;8:14-26
|How to cite this URL:|
Grover HS, Hans VM, Hans M. Delineating periodontal research: Climb is worth the view. J Int Clin Dent Res Organ [serial online] 2016 [cited 2020 Jan 28];8:14-26. Available from: http://www.jicdro.org/text.asp?2016/8/1/14/176246
| Introduction|| |
Periodontal research has been increasing in the past few years at an exponential rate. A huge amount of data is published every year that aims to unravel the mysteries of this highly prevalent inflammatory disease that can have an impact on the quality of life. Over the last two to three decades, there have been huge advancements in our understanding of the periodontal disease process, its etiology, pathogenesis, microbiology, diagnosis, and various treatment modalities. It is indeed a daunting task to compile all the information gathered through these research activities and apply it not only to improve the quality of treatment that we provide but also prevent this highly complex multifactorial disease, periodontitis.
The colossal amount of ongoing research also raises certain questions. Are all the data that we collect from this research worth the effort? We need to ponder on whether the time and effort that we place in enhancing our knowledge of periodontal disease is ultimately going to be useful for patients in general or are whether we just scanning the dirt with no gold? In this review, we will look into the ongoing research and how it is changing our perspective about periodontal disease, its treatment, and most importantly its outcome [Figure 1]. Different areas of periodontal research would be touched briefly and the need for such research would be weighed for its benefits and future applications.
| Etiology of Periodontal Disease|| |
Decades of our knowledge have led us to understand that periodontitis is caused by specific bacteria or a group of bacteria that occur together. , New paradigms of theories explaining the etiology of periodontal disease keep on appearing when the previous one fails to explain the known factors adequately or some new evidence appears. Three main hypothesis have been proposed to explain the role of microbiota in the etiology of periodontal disease: Nonspecific, specific, and ecological. ,, The nonspecific plaque hypothesis proposed that accumulation of bacteria adjacent to the gingival margin led to initiation of inflammation, which later on led to periodontal destruction. In other words, the amount of plaque determines the disease expression.  The specific plaque hypothesis on the other hand, does not consider all species within plaque pathogenic but rather overgrowth of specific bacteria alluded to disease.  The ecological plaque hypothesis presented a totally different perspective. It explained that the change in local environment leads to growth of pathogenic bacteria, which tilt the balance from health to disease.  Once the microbes are implicated for causation of periodontitis, more questions spring up, a few of which will be dealt in this section.
Periodontitis: Pathogenic or opportunistic infection?
Early work on the origin of periodontal infection focused on whether periodontal infection was indigenous or exogenous in origin.  It is important to know the source of infection to plan the preventive treatment we can provide to the patient. If the infection is indigenous, the chances of removing the organism from the oral ecosystem are grim, whereas if the infection is exogenous treatment and prevention will both focus on total removal of the organism from the oral cavity. The information gathered from years of research has helped us understand that oral flora, although of a commensal nature, becomes pathogenic as the inflammatory response of the host is altered thereby increasing the host susceptibility.  Thus, to conclude the overgrowth of pathogenic bacteria leads to disease; it is likely that the host response to accumulation of indigenous bacteria leads to the creation of an environment that causes the overgrowth of pathogenic bacteria. ,
The red complex: Accused or convicted?
More than 750 species have been identified in the subgingival plaque.  Socransky et al. identified five complexes of bacteria, based on their frequency of occurring together in the subgingival plaque.  These complexes were yellow, purple, green, orange, and red [Figure 2]. The red complex, the most pathogenic of all, includes Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia. It has been implicated in the initiation and progression of chronic periodontitis. Also, the presence of the red complex has been associated with bleeding on probing, which is a sign of active periodontal disease.  Although dental plaque has a complex structure, with multiple species, all the bacteria are not disease-causing. Various studies have indicated that the red complex bacteria possess a variety of virulence factors that directly or indirectly cause periodontal tissue damage, which makes them more aggressive than other species present in the subgingival plaque. ,,
Of the diverse virulence factors P. gingivalis possesses, the most important are its proteases, which are commonly called gingipains. The Arg-gingipain (RGP) and Lys-gingipain (KGP) cause dysfunction of inflammatory responses, along with degradation of various connective tissue proteins. , T. forsythia, another anaerobic gram-negative rod, is frequently isolated along with P. gingivalis.  T. forsythia holds certain putative virulence factors that comprise hemagglutinins, sialidase and trypsin-like protease.  Also, the cell surface-associated and secreted protein (BspA) of T. forsythia has been associated with alveolar bone loss in mice.  It has been observed that a mixed infection of P. gingivalis and T. forsythia shows synergistic pathogenesis with a more virulent expression of disease in animal models. 
T. denticola, present within the surface layers of the subgingival plaque is frequently isolated, along with P. gingivalis in progressing periodontal lesions.  There is a symbiotic nutrient relationship that exists between these periopathogens. T. denticola owns a chymotrypsin-like proteinase, dentilisin, which not only causes tissue destruction but also helps in its coaggregation with P. gingivalis.  A study in a rat model reported that a mixed infection of P. gingivalis and T. denticola produces a significantly more horizontal and interproximal bone loss than their individual infections.  These bacteria are pathogenic individually but their virulence increases manifold when they occur together.
Most therapeutic modalities against periodontitis aim to eradicate the pathogens from within the periodontal pockets. Understanding the complexities of interbacterial relationship and their role in the progression of periodontal disease may facilitate the newer treatment modalities. A few of these modalities include passive immunization, probiotics, and antagonists to prevent the adherence of bacteria to each other.  Recent research has identified organisms that are antagonistic to periopathogens. Staphylococcus aureus and Streptococcus mutans inhibit the growth of P. gingivalis and T. denticola. , Certain probiotic strains of bacteria such as Streptococcus and Actinomyces inhibit the growth of P. gingivalis.  Such treatment modalities underline the importance of periodontal research in identification of the bacteria responsible for causation of disease and combating them by novel means.
Tissue invasion: Favoring the enemy
Periodontal pathogens have the capability to invade the gingival tissues that enable them to cause inflammation within the tissues. These pathogens include Fusobacterium nucleatum, P. gingivalis, T. forsythia, and T. denticola.  These bacteria interact with epithelial cells and cause rearrangement in the cellular machinery so that they can gain entry into nonphagocytic cells.  P. gingivalis activates the actin filament rearranging protein, coflin, through its serine phosphatase SerB to enter the epithelial cells.  This invasion takes 15 min after which bacteria replicate and accumulate within the perinuclear area and later spread to the adjacent cells and tissues. , It is also notable that these epithelial cells invaded by P. gingivalis remain viable and do not show signs of necrosis. 
F. nucleatum and P. intermedia invade both human gingival fibroblasts and endothelial cells. , Once within the cytosol, F. nucleatum rapidly fuses with lysosomes and is rapidly degraded within the epithelial cells.  This transfer of bacteria to the endolysosomal compartment induces the release of interleukin-8 (IL-8) from gingival epithelial cells, which activates neutrophil migration into the area.  The host has other mechanisms also for its protection. The continuous shedding of epithelial cells may provide protection against invading bacteria but the comparatively lower shedding rate of the gingiva provides enough time to the bacteria to invade the underlying connective tissue.  The proteases released by P. gingivalis and T. denticola dissolve the basement membrane, apart from collagen and elastin of the connective tissue. 
Bacterial invasion of the periodontal tissue has been known since decades but how it eventually causes destruction was unknown. The research in this field has shown that invasion by P. gingivalis causes T-cell infiltration and was positively associated with alveolar bone loss. , It has been proposed that bacterial invasion of the gingival tissues plays an important role in the initiation of periodontitis by causing persistent chronic inflammation.  Knowledge of the mechanisms of initiation of periodontal disease is instrumental in developing preventive and therapeutic approaches toward periodontitis. Potential therapeutic modalities to prevent tissue invasion by periopathogens may include strengthening of the epithelial, physical, chemical, and immunological barriers. For example, epithelial antimicrobial peptides produced by gingival epithelial cells provide a chemical barrier against periopathogens.  The development of such defense molecules exogenously will be a massive therapeutic leap, which the present research is aiming at.
Aggregatibacter actinomycetemcomitans: Too aggressive?
A. actinomycetemcomitans is a gram-negative anaerobic organism, which most frequently occurs as a rod. It can also exist in the coccoid form, which appears like Morse code.  Its presence in periodontal pockets has been associated with localized and generalized aggressive periodontitis. , Having an array of virulence factors [Figure 3], the most important being leukotoxin, it is associated with an early and aggressive destruction of the periodontium.  This leukotoxin can kill polymorphonuclear neutrophils (PMNs), macrophages, and peripheral monocytes, apart from epithelial and endothelial cells.  The endotoxin of A. actinomycetemcomitans has the potential to modulate host responses as well as carry out tissue destruction. Its endotoxin stimulates macrophages to release interleukin-1(IL-1) and tumor necrosis factor-α (TNF-α), which are responsible for alveolar bone resorption. 
|Figure 3: virulence factors of periopathogen Aggregatibacter actinomycetemcomitans|
Click here to view
The implication of A. actinomycetemcomitans for causing aggressive periodontitis has helped in several ways. Since a particular organism is involved, controlling the organism will control the disease. Also, apart from the mechanical removal of plaque, antibiotics can be used to eradicate A. actinomycetemcomitans from the periodontal pocket and tissues. Vaccines can also be developed against A. actinomycetemcomitans, which can protect susceptible patients against the rapid loss of periodontal tissues. Thus, the research has not only proved a strong role of A. actinomycetemcomitans in aggressive periodontitis but also opened a number of avenues where future research can be directed.
Novel pathogens: Hidden threat
Identification of microbiota within the oral cavity started from culture-based methods and has evolved over decades to molecular investigations. Recently, the cloning and sequencing of ribosomal 16S have helped in the identification of previously unknown bacteria. Certain species have been associated with periodontitis and termed periopathogens, which include: P. gingivalis, T. forsythia, Actinomycetemcomitans, Prevotella intermedia, Prevotella melaninogenica, F. nucleatum, Parvimonas micra, Eikenella corrodens, Prevotella nigrescens, Capnocytophaga gingivalis, Treponema denticola, Treponema socranskii, Eubacterium nodatum, and Campylobacter rectus.  Several newer organisms have been proposed that can be added to the list, some of which are Dialister pneumosintes, Solobacterium moorei, and Filifactor alocis. The presence of D. pneumosintes in 83% of the patients with severe periodontitis has led to a suspicion that it might be a periodontal pathogen. Ghayomi et al. have isolated and identified D. pneumosintes from periodontal pockets via 16s ribosomal RNA polymerase chain reaction.  Solobacterium moorei, a gram-positive anaerobic bacterium has been isolated from patients with halitosis and refractory periodontitis. In a study, eight subjects with halitosis harbored S. moori on the dorsal surface of the tongue, whereas there was a complete absence of the same in normal subjects. 
Filifactor alocis is a gram-positive obligatory anaerobic organism that shares its virulence properties with F. nucleatum. It is found in higher numbers in both chronic and aggressive periodontitis patients compared to healthy individuals. It is so prevalent in periodontitis patients that it has been suggested as a marker for periodontal disease.  With all the focus on the red complex, the other bacteria that might be equivalently pathogenic seems to have been ignored. But with pathbreaking research in microbiological methods, we are identifying newer pathogens of the oral cavity. Better characterization of oral microflora will provide a brighter chance for the treatment and prevention of periodontal diseases.
Viral etiology of periodontitis: To be or not to be?
Our knowledge of viral infection has increased tremendously over the years with newer viruses being identified and characterized. With newer techniques of identification, viruses are now being associated with periodontitis too. One of the most researched viruses in this aspect is herpes virus. Several herpes virus species exist in the saliva of most individuals, frequently acquired via salivary contact in early life.  The presence of two of the herpes virus species, Epstein-Barr virus and cytomegalovirus in the saliva can also originate from periodontitis lesions. ,
Traditionally, periodontitis was considered to be an infectious disease of bacterial origin. But several characteristics of the disease such as site specificity and several other clinical features could not be explained by its bacterial etiology. On the other hand, a combined herpes virus-bacterial periodontal infection may account for several of these unexplained features of the disease  although such an explanation is still hypothetical with more research required in this direction. Various researches have revealed that herpesviruses have a close relationship with periodontal disease. One of the herpesviruses, Cytomegalovirus, has been detected within gingival monocytes, T cells of periodontitis patients, and biopsies of periodontitis patients. , Cytomegalovirus infection has also been linked to active periodontal disease in several studies. , The research in this field is still evolving and increased familiarity of the immunovirology of herpesviruses in periodontitis may lead to more effective preventive and therapeutic interventions. Development of a future vaccine against herpes virus might provide a novel therapeutic intervention for periodontitis.
| Pathogenesis of Periodontal Disease|| |
The pathogenesis of any disease is its mode of origin and development. Considerable research has focused on defining the pathways of pathogenesis of periodontal disease [Figure 4]. However, the information remains incomplete and further clarifications are required regarding many aspects. Despite the existence of histological similarities between gingivitis and periodontitis, periodontitis cannot be considered to be the inevitable consequence of gingivitis; at least this is not what the evidence says.  Different individuals show different ways of progression of disease, some might not progress to periodontitis from gingivitis, whereas others cross over rapidly. Some patients exhibit a rapid loss of periodontal ligament and clinical attachment levels, whereas in others the disease might progress slowly.  Understanding the pathogenic mechanisms helps us to understand the activity of disease and different responses of individuals. The current research is focusing on fluctuation of host defense mechanisms and other contributing factors, all of which are not clearly defined.
Immune response: Enemy within
There has been constant progress in understanding the complexity of human immune response, particularly in the context of periodontal disease. The delineating molecular knowledge about the host bacterium interaction that occurs within the periodontium gives a brief explanation as to why some individuals do not develop the disease, whereas others succumb to it. It has been already established that the accumulation of bacterial plaque within the gingival sulcus triggers gingival and periodontal diseases.  Nonetheless, it is the resistance of the host and the immune response that, in turn, determines the disease progression.
Innate immunity acts as a first line of defense to eradicate the potential pathogens.  During the healthy state of gingival sulcus, a transudate fluid, the gingival crevicular fluid bathes the sulcular area. This transudate has low protein and cellular contents. As the inflammation initiates within the sulcus, the transudate fluid switches to exudate with influx of PMNs, along with high protein content.  This production of inflammatory exudates is the primary nonspecific defense mechanism to wash out the irritants.
The first cells to come in contact with microbes and bring about inflammatory changes are the resident cells.  The resident cells (for example, mast cells) are rich in histamine, leukotrienes, serotonin, heparin, and antimicrobial peptides. The release of these substances brings about the initial inflammatory changes increasing the influx of other inflammatory cells into the area such as PMNs and macrophages.  As the first defense fails, chronic inflammation ensues by involving cells of adaptive immunity.  The cell-mediated immunity brings about drastic immunological changes. The regulatory T cells amplify or suppress the immune response through costimulatory molecules acting on effector B and T cells. Once the effector T cells are activated, they carry out the killing of infected or tumor cells.  B cells, on the other hand, are involved in antibody synthesis against particular pathogens.  In general, cell-mediated immunity has a more specific immune reaction toward particular microbes.
Substantial literature has been added that describes the characteristic of adaptive immunity response against periopathogens. One of the high-risk periodontal diseases, aggressive periodontitis, is rapidly progressing with enormous periodontal destruction that is not commensurate with the amount of local factors.  In aggressive periodontitis, the T cells have a decreased CD4/CD8 ratio when compared to healthy patients suggesting an altered immunoregulation contributing to disease expression.  Specific immune responses develop following recovery from an infectious agent, which leads to decreased susceptibility to a subsequent attack by the same microorganism.
Antibodies are the proteins produced by B cells that are unique in combating extracellular-specific antigen. A plethora of research has detailed this humoral response ranging from periodontal health to disease. It has been confirmed that there is a local production of specific antibodies within the periodontal pocket as the levels of antibodies inside the sulcular fluid are significantly higher than the serum.  As the healing starts after treatment, the antibody levels decrease in the sulcus.  Elevated levels of immunoglobulin G (IgG) antibody were observed in the sulcular fluid of chronic periodontitis patients while in aggressive periodontitis patients, more specifically IgG1 and IgG4 levels were significantly elevated. , The local antibodies also exhibited a specificity to A. actinomycetemcomitans in aggressive periodontitis patients. Similarly, the sulcular fluid samples of chronic periodontitis patients exhibited elevated levels of antibodies against P. gingivalis. 
While a large amount of data is available about the robust immune response against A. actinomycetemcomitans and P. gingivalis, limited data are available regarding the antigenic diversity that contributes to the chronicity of the host parasite interaction seen in periodontal disease. As we gather more data from research focused on immunobiology of the host, we gather more information on identifying the potential antigenic targets for vaccine development and also modulating the host to produce immune response that targets specifically pathogens, saving the host from tissue destruction.
Proinflammatory cytokines and mediators: Sentinels of destruction
The interaction of bacterial virulence factors activates the host cellular response, along with cytokines and proinflammatory mediators such as PgE2. These mediators promote the activation of tissue-derived matrix metalloproteinases, which carry out destruction of the extracellular matrix and alveolar bone.  Cytokines are the molecules released by host cells, which bring out the alteration in the neighboring cells, thereby affecting their function. One of multifunctional cytokines playing an important role in the pathogenesis of periodontal disease is IL-1. It promotes the accumulation of inflammatory cells, resorption of bone, and stimulates the release of matrix maetalloproteinases.  IL-1 levels are elevated in gingival tissues and sulcular fluid in periodontally diseased sites compared to healthy sites. 
Another proinflammatory cytokine that has been vastly studied in the context of its role in periodontal disease is TNF-α. It shares several of its biological activities with IL-1, which include matrix metalloproteinase activation, eicosanoid production, and bone resorption.  PgE2 is a vasoactive eicosonoid that has been implicated in alveolar bone resorption in several studies.  The level of PgE2 rises as the periodontal disease progresses and the levels come down with treatment and the healing of periodontal tissues.  Thus, a lot of research has correlated the increased levels of proinflammatory cytokines and mediators with periodontal destruction. This has opened up a new avenue in periodontal treatment, which is host modulation.
Several drugs have been reviewed for their role in reducing the levels of proinflammatory mediators in periodontal tissues to pause the host-mediated tissue destruction. Nonsteroidal antiinflammatory drugs have been used systemically as well as locally to reduce the levels of PgE2 and thus, control periodontal tissue destruction. , Subantimicrobial dose doxycycline (Periostat) directly inhibits matrix metalloproteinases, thus reducing extracellular matrix destruction and alveolar bone resoprtion.  Further research is focusing on several newer drugs such as metformin, which is also being tested for host-modulating effects on periodontal tissues, whereas otherwise it is an antidiabetic drug. 
Genetic factors: Fate sealed
The tissue destruction seen in periodontitis is a result of direct toxicity of bacterial products, along with the chronicity of host responses toward these products. This chronic immune response is detrimental to the health of periodontal tissues. Thus, the destruction seen in periodontitis can be attributed to a dysregulated immune response. The host response of an individual can be traced to his/her genome. Numerous researchers have attempted to identify candidate genes responsible for genetic predisposition toward aggressive periodontitis and severe chronic periodontitis. , The focus on genetic predisposition has come after an observation that certain individuals are more susceptible to periodontitis, whereas others are resistant when all other contributing factors are similar. Some individuals have an aggressive immune response, whereas others generated a lower response.
Several genes have been implicated in the manifestation of aggressive periodontitis, which includes TNF-α, IL-1β, FcgRIIIb NA1/NA2, and HLA-A9. ,,, IL-1β SNP has been also associated with chronic periodontitis. In many populations, a link between IL-1β polymorphism and the susceptibility to periodontitis has been demonstrated. But what do we achieve even if we find an association between certain genes and periodontal disease? There are several aspects of this association; one is identification of the susceptible host. For this purpose, a genetic screening test-periodontal susceptibility test (PST)-has been developed. This test identifies variations in IL-1α and IL-1β gene and a positive test indicates increased susceptibility to chronic periodontitis. , The susceptible individuals thus identified can be provided with more rigorous oral care and an increased number of maintenance visits. Another aspect is that after the identification of susceptible individuals, they can be made less susceptible. This can be done via vaccination, host modulation, and perhaps gene therapy. Although gene therapy appears to be a distant dream, research is moving in right direction and at a faster pace.  The near future may see individuals with replaced defective genes and a possible disease-free society.
Environmental factors: Effectual influence
Apart from the plaque being the primary etiological agent for periodontal disease, the genetic and environmental factors modulate the expression of disease. One of the major environmental factors that has been identified as a risk factor for periodontitis is tobacco smoking.  As the number of pack/years of exposure to smoking increases, so does the severity of periodontitis.  Although there is a decrease in gingival inflammation and bleeding on probing because of the vasoconstrictive effect of nicotine, a major constituent of tobacco smoke, there is an increased prevalence and severity of periodontal destruction.  As a result of toxins within tobacco smoke, there is an altered neutrophil response to infection. There are increased levels of proinflammatory cytokines (IL-1, TNF-α, and PgE2) inside the periodontal pocket.  Not only is smoking associated with chronic periodontitis but it has also been associated with increased disease severity in the aggressive form of periodontitis. 
Several studies have demonstrated a reduced clinical response to nonsurgical periodontal treatment in smokers compared to nonsmokers.  Similar findings were observed with surgical periodontal therapy, with lower pocket depth reduction and lower gain in clinical attachment levels in smokers compared to nonsmokers.  The effect of constituents of smoke on the individual cells of the periodontium has also been studied.  Such detailed research on the effect of smoking on periodontal tissues has demonstrated a clear link between the two and established smoking as a risk factor for periodontal disease. Since smoking is a modifiable risk factor, the patient can be motivated to quit smoking and better maintenance plans can be instituted for smokers with periodontal disease.
| Periodontal Medicine|| |
William Hunter in 1900 claimed that focal infection of the teeth can lead to subsequent infection in other parts of the body, either by translocation of infection-causing bacteria or by a release of toxins into the circulation.  This theory led to unreasonable extraction of diseased teeth and was later discarded due to the lack of evidence. It however, laid the foundation that the "mouth is attached to body." In the past few decades, various epidemiological studies emerged that associated periodontitis with systemic health conditions such as cardiovascular disease, diabetes, and preterm labor. ,, There is expanding evidence that associates chronic inflammation seen in periodontitis with an array of systemic diseases.
Following injury and inflammation in one part of the body, there are increased acute phase reactants (for example, components of the complement system, C-reactive proteins). These acute phase reactants have been used as a risk marker for a variety of systemic diseases.  Chronic diseases such as periodontitis can be a nonending source of such acute phase reactants.  Chronic periodontitis patients exhibit elevated levels of acute phase reactants that reduce with periodontal therapy and adjuvant use of anti-inflammatory drugs. , The research in this field has been never-ending although here the focus will be on systemic conditions where the results are more or less conclusive.
Cardiovascular disease: At the heart of quandary
The data suggesting an association between cardiovascular disease and periodontal disease are overwhelming. Several systematic reviews and meta-analyses have depicted an association between the two diseases. , For many years, we believed that cardiovascular disease is a lifestyle disease but the role of infection as a contributing agent has been in focus lately. Some pathogens have been incriminated for the development of atherosclerosis. The lipopolysaccharides (LPS) derived from pathogenic bacteria have been found to be directly toxic to endothelial cells, causing them to express adhesion molecules and hence, the adhesion of monocytes. Also, LPS converts macrophages to foam cells, which play a central role in atherosclerotic plaque development. 
In a study after the adjustment of other risk factors, it was found that common infections such as urinary, respiratory, and periodontal infections significantly increased the risk of carotid artery atherosclerosis.  Several periopathogens, namely, A. actinomycetemcomitans, P. gingivalis, T. forsythia, and T. denticola have been identified in atherosclerotic plaques.  Many studies have shown the presence of multiple species rather than one, confirming that a mixed infection is more pathogenic. There are conflicting reports also where periodontal pathogens have been found in healthy arteries too or the absence of these bacteria has been found in atherosclerotic plaques from patients with periodontal disease.  Therefore, it has been concluded that periodontal bacteria could lead to the propogation of atherosclerosis in an already damaged vessel.
With a lot of research showing an association between the two diseases, many questions remain unanswered. The coexistence of these diseases could be coincidental due to the sharing of common risk factors or they may have a cause-and-effect relationship. Cardiovascular disease leads to high morbidity and mortality. Identification of periodontal disease as a risk factor is important for preventive measures to be taken for cardiovascular disease. This can significantly lower the cost of management of cardiovascular diseases.
Diabetes mellitus: The reciprocal deal
There exists a bidirectional relationship between periodontal disease and diabetes mellitus. While periodontal disease has been defined as the sixth complication of diabetes, it has also been established that periodontal disease worsens the glycemic control of diabetic patients.  Poor glycemic control is a major contributing factor for periodontal disease as chronic hyperglycemia leads to impaired macrophage and neutrophil function as well as the accumulation of advanced glycation end products that interfere with normal healing.  Since periodontal disease occurs in spurts with a period of disease progression followed by quiescence, impaired wound healing can lead to more rapid destruction.
Two studies focusing on the role of periodontitis on diabetic control showed that type 2 diabetic subjects with periodontal disease are at threefold higher risk for developing diabetic complications than those with healthy gums. Also, the risk of death from diabetic nephropathy and coronary artery disease was threefold in subjects with severe periodontitis. , Periodontal disease, being an immune-inflammatory disease, causes an increase production of proinflammatory mediators and acute phase reactants. Several studies have shown a manifold increase in the concentration of these mediators in the serum as well as in periodontal tissues as the periodontal disease progresses. Some of these mediators such as IL-1, IL-6, and TNF-α have been associated with insulin resistance.  A majority of the studies show an improvement in glycemic control after the periodontal disease is treated. , A recent review has pointed out that although the glycemic control after periodontal treatment was modest, the reduction was sufficient to reduce the risk of microvascular complication of diabetes. 
Awareness of the periodontist toward the interrelationship of both these diseases helps in the identification of undiagnosed diabetic patients in the dental setup. The causal effect of periodontal disease on glycemic control underlines the importance of improving oral health in diabetic patients. The research in this field has a significant influence on reducing complications in diabetic patients and improving the quality of life in such patients.
Preterm birth: Short on term, high on risk
Preterm birth, a major cause of neonatal mortality, is any delivery that occurs after 23 weeks and less than 37 weeks. Many risk factors have been attributed to it, which include maternal age, tobacco, maternal body mass index, and multiple pregnancies.  Offenbacher in 1996 suggested that periodontal disease also could pose a risk for preterm births.  Several studies have been conducted since to prove an association between the two. Many studies have shown a positive correlation where the high prevalence of severe periodontitis is associated with preterm birth. , The presence of periodontal microflora such as F. nucleatum and P. gingivalis has also been detected in the amniotic fluid as well as placenta. Within the uterus, these organisms can invoke an inflammatory response, which could induce preterm labor. 
In 1998, Offenbacher suggested that cytokines such as TNF-α and IL-1 produced locally in the periodontal tissues could be released into the circulation. These circulating cytokines can promote inflammation in the gravid uterus, causing an adverse pregnancy outcome.  Several interventional studies were conducted to monitor the effect of periodontal treatment on pregnancy outcomes. Contradictory results and varied conclusions have been derived from such studies. A recent meta-analysis however, found that periodontal treatment did not reduce the rate of preterm births. This could be due to the heterogeneity of the studied population, socioeconomic variability, and periodontal status definition. 
Despite conflicting results, periodontal treatment is safe for pregnant females and should be instituted in such females for improved periodontal status. This would remove the impact of periodontal disease on preterm birth incidence. The research on the correlation between these two has improved the coordination between obstetricians and periodontists. The early referral and treatment of periodontitis will be beneficial and improve the chance for a normal pregnancy outcome in high-risk patients.
| Periodontal Regeneration|| |
Periodontal disease leads to the destruction of attachment of the tooth to the surrounding alveolar bone. When untreated, it eventually leads to tooth loss. The current treatment strategy focuses on plaque removal and the promotion of tissue repair. However, the complete regeneration of the lost periodontium remains a challenge. Regeneration is the reconstitution of the lost part in a way that its architecture and function are completely restored.  There is an evidence that some regeneration of the periodontium occurs after therapy, which is usually partial.  The current evidence available on periodontal regeneration is mainly on bone grafts and guided tissue regeneration. , Newer research is however, focusing on other dimensions of regeneration including growth factors, stem cells, and gene-based approach of tissue engineering.
Growth factors: Manure for regeneration
Growth factors are a large family of small proteins that modulate cell responses such as proliferation, chemotaxis, cell adhesion, and differentiation. Different growth factors have different targets in wound healing and very specific functions. In terms of periodontal wound healing, platelet-derived growth factors, vascular endothelial growth factors, transforming growth factor, insulin-like growth factor, and bone morphogenetic proteins (BMPs) have been extensively studied. Transforming growth factor-β (TGF-β) stimulates cell proliferation in periodontal ligament cells and is a potent stimulator of chemotaxis in gingival and periodontal ligament fibroblast. , There is considerable evidence based on animal studies that TGF-β may stimulate periodontal regeneration. The substantiation of these results from human clinical trials of TGF-β is still lacking. 
BMPs stimulate cell proliferation in endothelial cells, mesenchymal stem cells, and osteoblasts. , The clinical trials of BMPs for the regeneration of periodontal tissues in humans have shown positive results.  In general, several studies indicate that the application of growth factors promote tissue regeneration. Further research will elucidate the role of growth factors in the regulation of periodontal wound healing and regeneration. More clinical trials in this field will help in achieving the ultimate goal in periodontal therapy - complete regeneration of host tissues.
Stem cells: The tissue generator
With the identification of mesenchymal stem cells by Friedenstein et al. in the bone marrow, the option of tissue engineering emerged as a therapeutic option in medicine.  The same concept of tissue engineering can be applied for regeneration of the lost periodontium as a result of destructive periodontal disease. Numerous body sites could be a source for somatic or adult stem cells. Adult mesenchymal cells were previously thought to be developmentally restricted to certain cell lineage but recent research has shown that they have a broad differentiation potential. 
Dental stem cells were first isolated from human pulp tissues and were termed "postnatal dental pulp stem cells."  the gingiva is one of the most accessible sites for harvesting mesenchymal stem cells for periodontal regeneration. Other sites include exfoliated deciduous teeth and the periodontal ligament. , The research in the field of stem cell-based tissue engineering is still evolving and has not yet been performed in a routine clinical setting. The future direction of this research aims at searching vehicles for stem cell delivery and developing protocols for application of tissue engineering in the treatment of periodontal disease.
Gene-based therapeutics: Perplexity resolved
Tissue engineering aims to regenerate functional tissues by mimicking a series of events that occur during periodontal tissue formation and growth. Several approaches have been researched to achieve this seemingly impossible goal, one of which is gene-based therapeutics or gene therapy. Gene-based therapeutics is the transfer of genetic material to alter specific genes in the host to generate a therapeutic benefit.  Gene therapy can help in the modification of cells to provide a constant supply of multiple growth factors at the site of defect and help in regeneration. 
A controlled gene delivery through a local depot of genes can help in the controlled maintenance of encoded proteins at the regeneration site. Viral or nonviral vectors can be used for gene transfer into the target cells, which can then be delivered to a particular site with the help of implantable scaffolds, polymeric hydrogel systems, or microparticulate systems. , Although the research in this field is advanced, it is still not applicable to a clinical setup. Further research will lead to a pathbreaking therapeutic approach that will change the future course of periodontal therapy, especially periodontal regeneration.
| Research to Practice: An Evidence-based Approach|| |
Research and practice are considered to be entirely different and are usually not talked about together. However, the truth is that these two aspects of dentistry are interrelated and cannot be viewed separately. The conclusions derived from a thorough research should be applied for a good clinical practice to justify the treatment decisions. While taking decisions in a clinical setup, a practitioner should base his/her practice on concrete evidence from the literature. The unanswered questions in the clinic pave way for research in that field. Systematic review and meta-analysis are the hallmark of evidence since they are the compilation of completed studies, which have consistent methodology and their results are reproducible.  However, there are other aspects to decision-making [Figure 5]. These include clinical circumstances, patient preference, and the judgment of the practitioner. In the end it is the experience of the practitioner, which allows him/her to make a final decision on the treatment by weighing on the available evidence in existing circumstances, keeping in mind the patient's preference. 
Clinicians must constantly update themselves on the ongoing research in the field and change the treatment modalities as the new research with the highest level of evidence emerges. In the same way, researchers must focus on the current lacunae in our knowledge of the field and provide answers to improve practice. Thus, this delineating research is the foundation stone of good clinical practice.
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Conflicts of interest
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| Authors|| |
Dr. Harpreet Singh Grover graduated from King George's Medical College, Lucknow, in October 1985. He was awarded gold medal for his outstanding academic achievements. He did his post-graduation in Periodontics from prestigious King George's Medical College, Lucknow in 1988. He has presented a large number of papers and has chaired many scientific sessions at conferences. He has worked as Principal in Desh Bhagat Dental College and Hospital, Punjab. He is presently the Additional Dean and the Head of Department of Periodontology in Faculty of Dental Sciences, SGT University, Gurgaon. He also is the Editor Delhi state IDA journal, Executive Member (Indian Society of Periodontology) and also the Immediate Past President of the West Delhi Branch (IDA). He has more than 85 national & International publications to his credit.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]