22. Pathogenesis / Disease Activity: Pathogenesis and Inflammation
Rapid Search Terms
- Provide an overview of the pathogenesis of periodontitis. Describe the sequence of events in order of occurrence.
- Describe Page & Schroeder’s model in detail.
- Discuss Gingivitis
- Does all gingivitis become periodontitis? Is gingivitis a prerequisite for periodontitis?
- How do periodontal pockets form? Which tissues are destroyed first?
- List enzymes implicated in periodontal destruction and their origin. Do these enzymes have any therapeutic or diagnostic significance?
- What is RANKL and describe it’s significance?
- What are matrix metalloproteinases and which ones are significant in periodontitis?
- How can the host response be modified as a part of periodontal therapy?
Overview of the pathogenesis of periodontitis.
- Listgarten M. A. Nature of periodontal disease: Pathogenic mechanisms. J Periodontal Res. 1987; 22: 172-78
- Schroeder H: Discussion: Pathogenesis of periodontitis. J. Clin. Periodontol. 13:426-430, 1986. (Review)
- PAGE R & K. KORNMAN: The pathogenesis of human periodontitis: an introduction. Periodontology 2004 Vol. 14, 1997, 9-11
- KORNMAN K,R. PAGE & M. TONETTI: The host response to the microbial challenge in periodontitis: assembling the players. Periodontology 2000, Vol. 14, 1997, 33-53
- Kinane DF: Causation and pathogenesis of periodontal disease. Periodontol 2000. 25:8-20,2001 (Review)
- DARVEAAUN R, NET ANNER& ROYC . PAGE: The ,microbial challenge in periodontitis. Periodontology 2000, Vol. 14, 1997, 12-32
- PAGE R, S. OFFENBACHER, SCHROEDER, G. SEYMOUR & K. KORNMAN: Advances in the pathogenesis of periodontitis: summary of developments, clinical implications and future directions. Periodontology 2OW. Vol. 14, 1997, 216-248
The Page & Schroeder’s model.
- Page RC, Schroeder HE: Pathogenesis of inflammatory periodontal disease. A summary of current work. Lab. Invest. 34:235-249, 1976 (Review)
- Van Dyke TE, Offenbacher S, et al. What is gingivitis? Current understanding of prevention, treatment, measurement, pathogenesis and relation to periodontics. J Int Acad Perio 1:3-15; 1999. (Review).
- Page RC. Gingivitis. J. Clin. Periodontol. 13:345-355, 1986. (Review)
Progression from gingivitis.
- Schroeder HE, Lindhe J : Conversion of stable established gingivitis in the dog into destructive periodontitis. Arch. Oral. Biol. 20:775-782, 1975.
- Soames JV, Entwisle DM, Davies RM : The progression of gingivitis to periodontitis in the beagle dog. A histologic and morphometric investigation. J. Periodontol. 47:435-439, 1976.
The formation of periodontal pockets.
- Ritchey B, Orban B. The periodontal pocket. J. Periodontol. 23:199-213,1952.
- Takata T, Donath K : The mechanism of pocket formation – A light microscopic study of undecalcified human material. J. Periodontol. 59:215-221, 1988.
- Saglie, Carranza, Newman and Pattison: Scanning electron microscopy of the gingival wall of deep periodontal pockets in humans. J Periodontal Res. 1982; 17: 284-293
Enzymes implicated in periodontal destruction.
- REYNOLDS J & MURRAYC . MEIKLE: Mechanisms of connective tissue matrix destruction in periodontitis. Periodontology 2000, Vol. 14, 1997,144-157
- Van der Zee E, Everts V, Beertsen W: Cytokines modulate routes of collagen breakdown. J Clin Periodontol. 24:297-305, 1997.
- Lee W, et al. Evidence of a direct relationship between neutrophil collagenase activity and periodontal tissue destruction in vivo: Role of active enzyme in human periodontitis. J Periodont Res 1995; 30:23-33
- SCHWARTZ, Z., J. GOULTSCHIN D. DEAN & B. BOYAN: Mechanisms of alveolar bone destruction in periodontitis. Periodontology 2000, Vol. 14, 1997, 158.1 72
- Mogi M, J. Otogoto, N. Ota and A. Togari: Differential Expression of RANKL and Osteoprotegerin in Gingival Crevicular Fluid of Patients with periodontitis. J DENT RES 2004 83: 166
- Nonnenmacher C, K. Helms, M. Bacher, R.M. Nüsing, C. Susin, R. Mutters, L. Flores-de-Jacoby and R. Mengel: Effect of Age on Gingival Crevicular Fluid Concentrations of MIF and PGE2. J DENT RES 2009 88: 639
- Johnson RB, Serio FG, Dai X: Vascular endothelial growth factors and progression of periodontal diseases. J Periodontol 70:848-852, 1999
Modulation of the host response.
- Salvi GE, Lang NP. Host response modulation in the management of periodontal diseases. J Clin Peridontol 2005; 32 (Suppl. 6): 108–129.
- Bhatavadekar NB, Williams RC. Commentary: new directions in host modulation for the management of periodontal disease. J Clin Periodontol 2009; 36: 124–126
Overview of the pathogenesis of periodontitis.
Provide an overview of the pathogenesis of periodontitis. Describe the sequence of events in order of occurrence.
Topic: Nature of periodontal disease
Title: A. Nature of periodontal disease: Pathogenic mechanisms.
Source: J Periodontal Res. 1987; 22: 172-78
P: Discussion article on the nature of periodontal disease and pathogenic mechanisms.
D: The oral microbiota, one of the most complex in the body, comprises over 300 species. Of these, about 30 are routinely observed and account for the majority of the cultivable strains. Health of periodontal tissues is maintained in a relatively stable state through the establishment of host-parasite equilibrium compatible with minimal tissue destruction and ready replacement or repair of damaged structures. Alterations in this equilibrium may develop as a result of local or systemic changes that decrease host resistance or from qualitative/quantitative alterations of periodontal microbes which result in increased virulence. These upsets may account for “bursts of disease activity. Bacteria can contribute to periodontal disease by direct injury of the host tissues (toxins, enzymes, toxic metabolic end products) or they can also act indirectly by triggering host mediated responses that may result in self-injury.
Role of bacteria and host-mediated tissue injury is discussed in detail.
- Non-specific theory of plaque induced periodontal disease (Loesche): Sheer mass of microorganisms (MOs) generate sufficient noxious stimuli to induce inflammatory response in host. Seen in gingivitis.
- Certain forms of periodontal disease (AgP) caused by particular organisms which cause disease by various mechanisms
Direct toxicity: Variety of substances of bacterial origin which are capable of causing injury. They are usually of large molecular weight and may include some enzymes. Classically toxins have been divided in endotoxins and exotoxins.
- Exotoxins: proteins released by live microorganisms into their immediate environment where they can cause direct tissue injury. Some exotoxins have a specific affinity for certain cell types. Neurotoxins for nerve tissue, leukotoxins for neutrophils or epitheliotoxins for epithelial cells.
- produced by Aa , associated with outer membrane of A.a cell wall from which it may be shed as membranous vesicles
- shown to have correlation with periodontal disease.
- shown to readily lyse human PMNs (Brehni et al)
- able to kill human monocytes and weaken local host defense (Taichman et al)
Endotoxins: Lipopolysacchirides (LPS) which are structural components of Gram (-) bacteria. Their release occurs primarily after lysis of the cells. Endotoxins can exert a wide diversity of biological events, yet they share a common molecular structure. The linear molecule which is oriented perpendicularly to the bacterial cell surface consists of 3 distinct regions.
- Lipid A region which forms part of the outer half of the outer membrane of the cell wall. It is responsible for direct toxicity.
- Thecentrally located core polysaccharide
- The polysaccharide side chains, where the 0-somatic antigensreside, extend peripherally beyond the outer membrane.
The carbohydrate components provide the lipid A with hydrophilic properties, which enhance its pathogenicity and may increase the resistance of the bacteria to phagocytosis.
- Enhance bone resorbing quality of osteoclasts
- They can also bind to surface of PMNs or macrophages which internalize the endotoxin. Subsequent internalization of the endotoxin causes the cells to release their lysosomal enzymes extracellularly, with resulting damage to the local tissues and the generation of peptides that are vasoactive and chemotactic for PMNs.
- Activate complement through the indirect pathway, with the consequent generation of complement-derived mediators of inflammation.
- Act as modulators of bacterial cell uptake by phagocytic cells, with the endotoxin able to promote or inhibit phagocytosis depending on concentration.
- Interfere with new attachment to denuded root surfaces.
Enzymes: Bacteria may exert pathogenicity in part through tissue invasion. Assorted enzymes may facilitate bacterial tissue penetration by removing various structural barriers and destroying host proteins that play a key role in host defenses like IgG’s.
- Proteases, specifically collagenase, hyaluronidase, and chondroitin sulfatase are of particular interest in periodontal disease. They can be found in spirochetes and black pigmented bacteroides.
- Metabolic products: End products of bacterial metabolism e.g. ammonia, indole, hydrogen sulfide, fatty acids also contribute to initiation and disease progression. Local changes in pH due to metabolism may also affect survival of certain microorganisms.
Effect on host cells: Bacterial enzymes may play an important role in neutralizing some of the oxygen -dependent antibacterial host defenses. Alterations in tissue oxygen levels may also favor the establishment of anaerobic infections that are associated with periodontitis. Bacterial protease can contribute to indirect injury of the host by destroying the functional activity of humoral antibodies directed against bacterial antigens.
Effect on bacterial cells: Bacterial interactions may play an important role in controlling the ability of microorganisms to colonize the tissues.
Host-mediated tissue injury
- Caused by inflammation by triggering variety of injurious stimuli including thermal, mechanical, chemical trauma
- Complement activation (IgG and IgM react with assorted bacterial antigens to form insoluable complexes). The formation of insoluble antigen- antibody complexes can activate the complement cascade with the resulting release of a number of mediators of inflammation into the extracellular environment. These can contribute to the influx of PMNs, the generation of additional vasoactive molecules and the outpouring of hydrolytic enzymes of lysosomal origin into the extracellular environment.
- The lipoteichoic acid and lipopolysaccharides of the gram-negative cell wall are able to activate the complement cascade through the alternative pathway. While activation of complement has an overall beneficial effect in proecting the host against bacterial attack, some tissue destruction is unavoidable. Tissue injury is due in part to the complement-mediated influx of phagocytic cells and the release of lysosomal enzymes, and the production, by lymphocytes and macrophages, of assorted lymphokines that are able to kill cells and resorb bone.
Title:Discussion: Pathogenesis of periodontitis.
Source: J. Clin. Periodontol.13:426-430, 1986.
Keywords: Pathogenesis, periodontitis
Purpose: Discussion on the pathogenesis of periodontitis
- Periodontitis is a local infectious disease caused and chronically maintained by a mixed, predominantly anaerobic bacterial infection of the subgingival portions of the periodontium. There are several difficulties in attempting to classify periodontal disease.
- Author suggests the use of gingival pocket depth as a diagnostic criterion because it is the precursor of periodontal pocket. A gingival pocket is a shallow pocket (1-2mm) and histopathologically is similar to the periodontal pocket. No doubt that the development of gingival pockets is due to bacterial plaque extending apically along root surface. Once a gingival pocket has formed, gingivitis is no longer reversible with simple reestablishment of OH. Any pocket lined with pocket epithelium presents a pathophysiologic situation of associated with high tissue permeabilityincreased tissue reactivityinfected w/ subgingival bacteriaunattainable to remove w/ OH.
- Transition from a gingival to a periodontal pocket is also due to the host response. There is no spontaneous shift back from the established lesion to the early.
- The width and shape of infrabony pocket is also important and should be assessed radiographically.
- Bone resorption occurs when plaque approaches 0.5 to 2.5 mm to the bone.Large bowel – shaped defects associated with periodontal pockets but extending further than the plaque radius, are probably related to lateral invasion of the soft tissues with plaque.
- BOP is useful only for the early stages of gingivitis since evaluating it is subjective with regard to severity.
BL:The diagnosis and the pathogenesis of a particular patient with periodontitis are usually unknown. Factors other than bacteria may influence the pathogenesis of periodontitis, like OH, food impaction, iatrogenic factors, all of which interfere with the host-parasite relationship
Title:The pathogenesis of human periodontitis: an introduction
Source: Periodontology 2000 Vol. 14, 1997, 9-11
Review:The major developments since the 1976 article by Page & Schroeder have been the discovery of the pathways through which bacteria activate host cells and systems in a manner that tissue destruction ensues and elucidation of the pathways through which the extracellular matrix components of the gingival and periodontal ligament are destroyed and alveolar bone is resorbed. Based on the current understanding, evidence is now sufficient for the development and application of new preventive measures, diagnostics and treatments targeted at blocking or altering these pathways.
Conclusion:Periodontitis is not a single homogenous disease but rather consists of a family of closely related diseases each of which may vary somewhat in etiology, natural history and response to therapy. There is a common chain of events of pathogenesis that is influenced by other factors including genetic and other risk factors may differ from one form of disease to another. Antigens and various other virulence factors, and in some cases invading bacteria, comprise the microbial challenge, and the host responds with an immediate inflammatory andimmune response that can influence the challenge. The host response results in production of cytokines, eicosanoids, other inflammatory mediators such as the kinins, complement activation products and matrix metalloproteinases, which perpetuate the response and mediate connective tissue and bone destruction. All of these events are influenced by disease modifiers, both genetic and environmental or acquired. The clinical picture observed is a result of the sum of these events. The severity and rate of progression of disease feedback to influence the nature and magnitude of the microbial challenge by, for example, influencing the pH and availability of oxygen and various nutrients in the periodontal pocket.
Title:The host response to the microbial challenge in periodontitis: assembling the players.
Source:Periodontol 2000. 1997 Jun;14:33-53.
Keywords:pathogenesis, host response
Purpose:To describe the histologic, cellular and molecular changes that occur during the transition from health to disease initiation and progression.
Discussion:Periodontitis is an infectious disease process. Bacteria and their products interact with the junctional epithelium and penetrate into the underlying connective tissue. Inflammation is caused and leukocytes (especially neutrophils) exit the post-capillary venules and end up in the sulcus. Collagen and other components of extracellular matrix are destroyed. Supra-g plaque extends apically and into the gingival sulcus, cells of JE are stimulated to proliferate and a gingival pocket is formed. At an early stage there is an enlarging leukocyte infiltrate and subsequently the lesion becomes dominated by B-cells that produce antibodies. As the disease worsens, periodontal pockets deepen, the components of the extracellular matrix of the gingiva and PDL are destroyed and alveolar bone is resorbed.
Scene 1. Acute bacterial challenge phase: the epithelial and vascular elements respond to the bacterial challenge.
Epithelial membranes, flushing by saliva and GCF protect the tissues from initial bacterial invasion. High turnover rate of epithelium is associated with rapid replacement of damaged cells.
When bacteria start to accumulate the release metabolic products (including fatty acids and the lipopolysaccharides (LPS) of Gram- bacteria) that activate JE cells to release various inflammatory mediators such as IL-8, IL-1αPG-E2, MMPs, TNF. Neural components of the epithelium influence the local vascular response. The bacterial products and epithelial response activate mast cells to release histamine and activate vascular endothelial cells to release IL-8 within the vessels to assist in localizing neutrophils.
Scene 2. Acute inflammatory response phase: the tissues respond to the early signals.
The wide extracellular spaces oh the JE allow neutrophil migration. The vascular leakage and activation of serum proteins such as complement, begin to amplify the local inflammatory response and produce further endothelial cell activation. Leukocytes and monocytes are recruited. Neutrophils exit the inflamed vessels and form a wall between plaque and gingival tissues. They are capable of killing bacteria by phagocytosis and prevent extension apical and lateral extension of plaque. PMNs are the majority of cells in the sulcus and mononuclear cells the majority of tissue infiltrate. IL-8 appears to be critically involved in PMN recruitment.
Macrophages produce mediators of the immune and inflammatory responses including IL-1β, IL-1 receptor antagonist, IL-6, IL-10, IL-12, TNF, IFN, MMPs, PG-E2 and chemotactic substances such as monocyte chemoattractant protein (MCP) and macrophage inflammatory protein (MIP).
Scene 3. Immune response phase: activation of mononuclear cells shapes the local and systemic immune response.
The changes in this phase are associated with periodontal pocket. Soon after inflammation starts the exudate from the vessels becomes predominated by mononuclear cells. T-cells, B-cells and plasma cells become evident in the tissues. T-cells produce IL-2, 3, 4, 5, 6, 10 and 13, TNF-IFN, TGFand chemotactic substances. Plasma cells become prominent in the tissues and produce immunoglobulins such as IgG, IL-6 and TNF-Fibroblasts are also activated and produce MMPs and tissue inhibitor of matrix metalloproteinases (TIMPs). Macrophages become effector cells and depending on the nature of the challenge secrete a restricted set of cytokines and express surface receptors that influence the antigen specific immune response that directly targets the pathogen. Their products alter the local environment in several ways. They produce chemokines that recruit additional monocytes and lymphocytes, they favor collagen degradation (through the production of specific factors such as PGE2 and MMPs) and they activate CD4+ T-lymphocytes and to differentiate to cytokine producing T cells that help B cell differentiation and antibody production.
IL-1 is a major mediator in periodontitis. IL-1β comes mainly from activated macrophages and fibroblasts. IL-1α comes mainly from keratinocytes of the junctional or pocket epithelium. Production is induced by LPS, other bacterial components and by IL-1 which is autostimulatory. IL-1 upregulates complement Fc receptors on neutrophils and monocytic cells, and adhesion molecules on fibroblasts and leukocytes. It enhances production of MMPs and PGs by macrophages, fibroblasts and neutrophils. Finally, it upregulates major histocompatibility complex expression by B and T cells and facilitates their activation, expansion, and Ig production.
Scene 4. Regulation and resolution phase: determinants of protective components in the sulcus and collagen balance in the tissues.
This phase represents the initial loss of attachment. T-cells and macrophages are producing selective subsets of prostanoids and cytokines that favor net loss of collagen and bone and less effective antibody production. The inflammatory mediator load increases and includes contributions by the fibroblasts of interleukins (16, 8), PGE2, TNFa, collagen, MMPs and TIMPs. Plasma cells are prominent.
Title:Causation and pathogenesis of periodontal disease
Source:Periodontology 2000. 25:8-20,2001
Keywords:Review, pathogenesis, periodontitis, gingivitis, microbiology
Purpose:To review the causation and pathogenesis of periodontal disease.
- Gingivitis must precede periodontitis, however, not all gingivitis progresses to periodontitis. Periodontitis has subject and site predilection, is a continuous process that undergoes exacerbation periods (“burst hypothesis”).
- Prevalence of periodontitis in the USA is 35% in adults (13% moderate to severe, 22% mild).
- Even in clinically healthy gingiva neutrophils are found in the junctional epithelium, PMN’s are attracted to the area by bacterial products and epithelial cells proteins, but if they become overloaded, “degranulation” and tissue damage occurs from toxic enzymes.
- Most individuals show signs of gingivitis 10-20 days after plaque accumulation
- In gingivitis, capillary beds open, there is a transudate and influx of inflammatory cells (macrophages and neutrophils as phagocytic cells; lymphocytes as immune response-related cells).
- Progression from gingivitis to periodontitis requires time, why some patients develop the periodontitis more readily than other is multifactorial including risk factors of particular bacterial species, age, socioeconomics and race, smoking, systemic disease, and genetics. Destructive processes are initiated by bacteria but propagated by host cells.
- Microorganisms of normal flora are present in gingivitis while exogenous or usual anaerobic seem to be implicated in periodontitis.
|The Classification of Kinane and Lindhe|
|Clinical condition||Histopathological condition|
|Pristine gingiva||Histological perfection (no inflammatory infiltrate)|
|Normal healthy gingiva||Initial lesion of Page and Schroeder (histologically has features of inflammatory infiltrate)|
|Early gingivitis||Early lesion of Page and Schroeder (lymphoid cells immediately below JE, loss of collagen)|
|Established gingivitis|| Established lesion with no bone loss or apical epithelial migration
Plasma cell density between 10-30% of leukocyte infiltrate
|Periodontitis|| Established lesion with bone loss and apical epithelial migration from the CEJ
Plasma cell density > 50% (plasma cells predominance reflects bone loss)
Title:The microbial challenge in periodontitis
Source:Periodontology 2000. 1997 Jun;14:12-32.
Keywords:dental plaque, biofilm, P. gingivalis, calculus, plaque, innate host response
P: The article reviews the composition of dental plaque, the ability of the bacteria to develop strategies that help them survive in the oral environment and the host defense system that constantly monitors the bacterial colonization status and prevents bacterial invasion into the tissues.
D: Biofilm: matrix-enclosed bacterial populations adherent to each other and/or to surfaces or interfaces.
Dental plaque formation: Microbial coating of a freshly cleaned tooth surface occurs rapidly. Two initial colonizers are Strep. GordoniiandA. naeslundii. Rapid colonization is favored by the ability of co-aggregation (two genetically distinct bacteria recognize and bind to each other; co-aggregation is based on the specific interaction of a proteinaceous adhesion produced by one bacterium and a respective carbohydrate or protein receptor found on the surface of another bacterium). Some bacteria can bind to each other without co-aggregation. Fusobacteriumspecies co-aggregate with all other oral bacteria, and thus play a major role to biofilm formation.
Dynamics of the dental plaque growth and host inhibition:
· Dental plaque growth is favored by inter-species cooperation, GCF and biofilm formation (aqueous channels).
· Host inhibition of supragingival plaque is mainly for the mechanical and anti-microbial properties of saliva. Subgingival plaque is inhibited by limited space and host innate defense system, which components are brought with the GCF.
· Plaque doubling times are more rapid in early development and slower in more mature films.
· Saliva:IgA, lactoferrin, lysozyme, peroxidase, antimicrobial proteins (histatins: antifungal and antibacterial activity)
· GCF:contains nutrients for bacteria. However, also contains lysozyme, vascular permeability enhancers (bradykinin, thrombin, fibrinogen), antibodies, lymphocytes
Role of the dental plaque biofilm in periodontal disease:
· Non-specific bacterial sheddingprobably represents the major mechanism by which the host is informed of the amount and type of bacterial colonization occurring on the biofilm.
· Bacteria can have direct or indirect effects (indirect: bacteria activate one cell type which in turn activate another) on host cells.
· Host cell response is grouped in myeloid (cytokine secretion) and non-myeloid (various inflammatory mediators).
· The dental plaque biofilm microbial composition can influence innate host inflammatory surveillance. LPS is one of the most probable mechanisms by which the host can sense different biofilm bacteria. Biofilm composition may result in a destructive response.
· The expression of bacterial virulence requires participation from the dental plaque biofilm. Host cell contact by pathogenic bacteria was shown to activate regions of the bacterial chromosome termed pathogenicity islands.
Potential role of P. gingivalis in periodontitis can be suppression of the innate host inflammatory response to bacteria.
LPS from this bacteria does not activate E-selectin, which would allow for vascular permeability of the endothelial cells for the PMNs to migrate and attack the bacteria.Pg has also shown to impair other bacteria from stimulation E-selectin expression. E-selectin can be activated indirectly by TNF-α and IL-β, however, PgLPS is a poor activator of these cytokines. This is in stark contrast to observations in clinical periodontitis of a large cellular inflammatory infiltrate and increased production of a variety of molecular mediators of inflammation.
· A gradient of IL-8 expression exists in normal tissue to guide leukocytes to the site of bacterial colonization (in presence of P.g, epithelial cells lose their ability to secrete IL-8, rendering the host unable to locate the source of microbial colonization).
· P.g is considered an opportunistic pathogen (may be a pathogen provided by the right combination of dental plaque).
· Aa and Pg invade host cells, providing not only a source of potential re-infection after mechanical debridement, but also a more difficult situation for the host to recognize the bacterial challenge.
Biofilms and therapy:
· Biofilms are notoriously resistant to surfactants and antibiotics as well as opsonization and complement –mediated phagocytosis and killing.
· The release of membrane vesicles and cell wall fragments serve to protect bacteria in the biofilm by acting as decoys that bind innate host defense components.
· The resistance of subgingival biofilms to normal host defenses has important consequences for the patient and for periodontal therapy. Physical removal is essential.
Microbial composition associated with different clinical states of periodontal health:
· Gingival health: Mostly gram-positive, streptococci and actinomyces, with about 15% gram-negative rod species. Bacterial load is relatively low in gingival health. An individual is more likely to manifest gram-negative bacteria and perio pathogens in healthy sites with increasing age and periodontal disease history.
· Gingivitis: Increased microbial load and a corresponding increase of gram-negative bacteria.
· Periodontitis: Increased total microbial load. Elevated proportions of P.g. T.f. and A.a. Elevated counts of the red and orange complex bacteria. Those species will determine the host response.
Clonal analysis has provided new insights into transmission and pathogenesis:
· Molecular epidemiological tools have identified more intraspecies variation than previously thought (restriction endonucleases analysis, restriction fragment length polymorphism, ribotyping).
· Transmission of periodontal bacteria occurs more likely through intimate contact, mostly within the family but not within general population communities (school, work environment)
· Clonal type analysis is being used to determine the presence of different clonal types. Various clonal types of the same bacteria can be found within the same host. Very limited number of clonal types have been identified due to the magnitude of samples necessary to prove clonality.
· The virulence of numerous clonal types is not clear.
Topic:pathogenesis of perio disease
Title:Advances in the pathogenesis of periodontitis: summary of developments, clinical implications and future directions
Source:Periodontol 2000. 1997 Jun;14:216-48
Keywords:periodontal pathogenesis, immune system, periodontitis
Purpose:To present the basic concepts and facts about pathogenesis of human periodontitis based on literature.
- Periodontitis is a family of diseases that differ in etiology but have a common underlying chain of events. The severity and rate of progression of disease feedback to influence the nature and magnitude of the microbial challenge. Many modifying influences may affect the onset and progression of disease or the response to various kinds of therapy. These influences may last for life, or vary in magnitude of effect at different times.
- Bacteria are essential but insufficient to cause disease, host factors are equally important. A.a. produces different clinical disease patterns in different people. This appear to be determined by combinations of factors like genetics and smoking.
- P. gingivalis, A.a. and B. Forsythus cause most cases of periodontitis except for acute necrotizing periodontitis (ANP).
- Subgingival microbial plaque behaves as biofilm. The behavior of the bacteria (mainly gram -) in it is different. They resist the host defense and also antibiotics. Physical disruption and removal are effective ways of dealing with biofilms.
- Periodontitis enhances the risk for various systemic diseases, including atherosclerosis, coronary heart disease, stroke and infants with low birth weight.
- Studies have shown that periodontopathic bacteria can be transmitted among individuals living in close contact.
- P. gingivalis is special in that its lipopolysaccharide does not activate the expression of E-selectin in vascular endothelial cells (which then triggers binding of leukocytes) therefore blocking the local neutrophil response to itself and other microorganisms in the plaque.
- The disease process is characterized by destructive periods followed by periods where this process subsides. There is experimented evidence that the responses in periodontal disease behave as if they occurred in a close system and many different balances can occur inside it through the biofilm/host interaction.
- As the microbial challenge increases clinical signs of inflammation in the gingival margin begin. The junctional epithelium plays a key role, initiating vascular endothelial responses and neutrophils migrate to the sulcus. Macrophages, lymphocytes and plasma cells are the majority of cells in the tissues. If the bacteria are not eliminated inflammation worsens and connective tissue and bone are destroyed. In this procedure host cells, for example fibroblasts or epithelial cells, can be activated to produce prostaglandin E2and matrix metalloproteinases resulting in destruction of the components of the extracellular matrix. These cause apical extension of the epithelium and pocket formation. Rete pegs of junctional epithelium to the connective tissue are also formatted.
- The stages of periodontitis according to its pathogenesis are initial, early, established and advanced lesions.
- Several studies agree to the conclusion that bone absorption is observed in a 2.5mm range around bacteria, but Schroeder pointed out lesions much greater than 2.5mm around single teeth.
- Thesusceptibility to periodontal disease differs between patients as some of them may only develop gingivitis whereas others with the same pathogens and comparable amounts of plaque may proceed to periodontitis, depending on several factors as the host’s response.
- Cytokines belong to a large protein family that comprises the major regulators of the immunoinflammatory response in periodontitis. Interleukins and chemokines are subfamilies of the cytokines, while interferon – and TGF-also belong to the cytokines.
- Both Th1 and Th2 clones of T helper cells can be met in periodontal lesions. The first one produces mostly interferon-γ and the second IL-6, IL-7 and IL-8. Whether any of these clones is associated with a specific clinical status is not yet clear.
- Prostaglandins and leukotrienes are major initiators of inflammation and PGE2is the major mediator of pathological alveolar bone destruction. The progress of the disease is not on dimensional or unidirectional. It is constantly being adjusted as a result of multiple and changing microbial challenges and multiple local and systemic host defenses. Clinically periods of quiescence are followed by bursts of destructive disease activity. The mechanisms that force the transition from one condition to the other are not completely known. Bone absorption is a result of uncoupling the tightly coupled process of bone resorption and bone formation, and more significant after 25-30 years of age.
- Periodontitis is a multifactorial disease. Bacteria are essential but insufficient to cause it. Several hereditary, host and other risk factors (such as diabetes mellitus, smoking, stress, HIV infection, socioeconomic factors, oral hygiene) coexist and modify the severity and type of the disease. Except for diabetes it is associated with major systemic diseases, such as cardiovascular disease and pre-term low birth weight delivery. Genetics has been shown to influence early onset periodontitis and adult forms. This influence is mediated through polymorphisms in the genes responsible for producing factors important in the pathogenesis of periodontitis (IL-1, IgG2m TNF-).
The Page & Schroeder’s model.
Describe Page & Schroeder’s model in detail.
Title: Pathogenesis of Inflammatory Periodontal Disease: A Summary of Current Work
Source: Lab. Invest. 34:235-249, 1976
Keywords:Gingivitis, Periodontitis, Chronic inflammation, Microbial plaque
Purpose: to discuss and review the current ant historic literature about the pathogenesis of periodontal disease
Discussion:Bacterial substances in plaque comprise the primary etiologic agent in gingivitis and periodontitis; however, many significant features of the disease cannot be accounted by this factor alone. There is a new belief that intrinsic host-related factors play an important role in the destructive process.
In the 18th and 19th centuries clinical observation was the predominant method used to understand the pathogenesis of the inflammatory periodontal lesion. In the late 19th century, there was a period of structural and morphologic analysis that began to examine the microscopic structures. During the past decade, the increased power of the electron microscope has provided additional insight into many of the cellular aspects and ultrastructural alterations.
Early concepts of pathogenesis
Gothieb (1946) presented the concept of “cementopathia”. He hypothesized that interference with continuous cementum deposits result in a lack of attachment of the collagen fibers of the gingiva and PDL. Goldman postulated an initial degenerative change in these fiber followed by epithelial cell proliferation and migration. Aisenberg (1948) showed that epithelial cells migrate apically between presumably normal connective tissue bundles. Cohen (1958), expressed the idea that the periodontal lesion may begin as a failure of the oral epithelium to replace the reduced enamel epithelium in the interproximal areas. James and Counsell (1927), and Fish (1935), introduced the zone of injury: Inflammatory cells accumulate in the JE and CT at the base of the sulcus. The zone of injury is located just coronal to the apical termination of the junctional epithelium.
Current view: the Page and Schroeder model.
Initial lesion (2-4 Days):
Lesion is localized to the gingival sulcus. The JE and most coronal portion of the CT are involved.
- Classic vasculitis of vessels subjacent to the JE
- Exudation of fluid from the gingival sulcus
- Increased migration of leukocytes (PMNs mainly) into the JE and gingival sulcus
- Presence of serum proteins, especially fibrin, extravascularly
- Alteration of the most coronal portion of the JE
- Portion of perivascular collagen disappears, and the resultant space is occupied by fluid, serum proteins (especially fibrin) and inflammatory cells.
Early Lesion (4-7 days):
- Presence and accentuation of the features described for the initial lesion (no clear cut dividing line).
- Accumulation of lymphoid cells immediately subjacent to junctional epithelium at the site of acute inflammation
- Cytopathic alterations in resident fibroblasts possibly associated with interactions with lymphoid cells.
- Further loss of collagen fiber network supporting the marginal gingiva. (Collagen loss may reach 60-70% within the reaction site)
- Beginning proliferation of the basal cells of the junctional epithelium
Established Lesion (2-3 weeks):
- Persistence of the manifestations of acute inflammation
- Predominance of plasma cells but without appreciable bone loss
- Presence of immunoglobulins extravascularly in the CT and JE
- Continuing loss of CT substance noted in the early lesion
- Proliferation, apical migration, and lateral extension of the junctional epithelium. Early pocket formation may or may not be present.
- Persistence of features described for the established lesion
- Extension of the lesion into alveolar bone and PDL with significant bone loss
- Continued loss of collagen subjacent to the pocket epithelium with fibrosis at more distant sites
- Altered plasma cells in the absence of altered fibroblasts
- Formation of periodontal pocket and surface ulceration
- Periods of inactivity and exacerbation
- Conversion of the bone marrow distant from the lesion into fibrous connective tissue (scar-like)
- The highly organized fiber bundles lose their characteristic architecture.
- Widespread manifestations of inflammatory and immunopathologic tissue reactions
- The author mentions the presence of plasma cell lesion, which is accompanied be extensive bone resorption even though the site of infiltration is some distance from the bone surface.
Title:What is gingivitis? Current understanding of prevention, treatment, measurement, pathogenesis and relation to periodontics.
Source:J Int Acad Perio 1:3-15; 1999
Keywords:gingivitis, pathogenesis, prevention, treatment, measurement
Purpose:To critically evaluate our current understanding of gingivitis.
Conclusion:Gingivitis: marginal inflammation of the gingiva comprising an inflammatory cell infiltrate,reversible destruction of collagen and the clinical appearance of redness and swelling.
Pathogenesis (from Page):
2-4 days: initial lesion, exudative vasculitis and loss of perivascular collagen. PMNsmigrate into the junctional epithelium and sulcus.
4-10 days: early lesion is characterized by a dense lymphocytic and mononuclear cell infiltrate
2-3 weeks: established lesion, is considered chronic gingivitis. Characterized by plasma cells.
Advanced lesion is characterized by the periodontal pocket, bone loss and eventually tooth loss.
Inflammatory cytokines play a prominent role:
1) IL-1β (secreted by monocytes and macrophages) upregulates adhesion molecules to permit cellular migration through vascular endothelium. Stimulates bone resorption and release of PGE2 and MMPs that degrade extracellular connective tissue.
2) TNF-α has similar activities as IL-1β, also triggers programmed cell death (apoptosis)
3) IL-1β and TNF-α are synergistic in causing release of vasoactive substances like histamine, serotonin, platelet activating factor and prostaglandins.
4) Prostaglandins induce vascular permeability and dilation that leads to redness/edema. Also induce the release of MMPs by monocytes and fibroblasts that cause tissue destruction.
5) MMPs degrade EC matrix
Rationale for prevention and treatment is to prevent the initiation or recurrence of periodontitis.
Chemical agents are desirable because patients are not effective at mechanically removing all plaque. CHX rinse is best on basis of efficacy, but long term use is limited by side effects. Other chemicals such as essential oils, triclosan, and stannous fluoride have been looked into as well and have moderate success. OTC products are good for those patients who are unable to achieve acceptable levels of mechanical plaque control but these patients should be monitored closely.
Objectivity and variability of indices: large margin of inter and intra examiner variability.
Baseline:Gingivitis and periodontitis represent the same pathogenic process, which manifests with varying degrees of clinical expression in different people. Overall, LTB4 in GCF is an excellent indicator of gingivitis, PGE2 is marker for periodontitis (although same levels can be seen in 4 weeks of gingivitis).
Source:J. Clin. Periodontol. 13:345-355, 1986.
Purpose:Review on gingivitis.
Mechanism of defense:
Epithelial barrier:oral, sulcular, junctional. As long as epithelial barrier is intact bacteria can’t enter the underlying connective tissue, nor can most noxious microbial substances gain access.
Saliva: the continuous secretion of large volumes of saliva provides a flushing action which aids in clearing bacteria from the oral cavity. Saliva contains antibodies, particularly secretory IgA which participate in the clearance of bacteria. Salivary agglutinins, may also play an important role by causing the clumping and clearance of bacteria via nonspecific interactions. Saliva also contains viable leukocytes derived from the peripheral blood that are capable of phagocytosis and killing.
Gingival fluid: Exudes from the gingival sulcus and it is a protective mechanism. It contains all of the substances present in blood serum but at more dilute concentrations, and its unidirectional flow provides a continuous flushing action. The components of the complement system are present in gingival fluid and these proteins are activated during the course of gingival inflammation. Gingival fluid also contains non- specific opsonins and antibodies specific for determinants of pocket bacteria. These too, participate in host defense by enhancing microbial killing and clearance.
Tissue turnover: The high level of tissue turnover is a defense mechanism. The regeneration potential is great and the periodontium can accommodate considerable amounts of damage without long-term deleterious consequences.
Neutrophils -PMNs.: important role in preventing gingivitis. Primary line of defense.
Gingivitis – inflammatory lesions confined to the tissues of the marginal gingiva. Periodontitis – inflammatory lesions extending into the deeper tissues.
On the basis of character of the exudate:edematous, serous, purulent, or necrotic.
Onthe basis of clinical manifestations: ulcerative, hemorrhagic, desquamative, or hypertrophic.
On the basis of etiology:plaque-associated, nutrition-associated, endocrine-associated, associated with generalized infections, or drug-induced.
On the basis of duration: acute or chronic.
Etiology:Microbial species associated with gingival health include S sanguis,and F naviforme. Bacteria involved in the etiology of gingivitis include specific species of Streptoccoccus, Fusobacterium, Actinomyces, Veillonella& Treponema & possibly Bacteroides, Capnocyto-phaga, and Eikenella.
Pathogenesis:Initial, early and established stages.
Pathogenesis in children: As plaque accumulates, clinical signs of inflammation either do not appear or their appearance is much delayed, and the inflammatory infiltrate consists mostly of T lymphocytes. The conversion to a B cell lesion does not appear to occur. The fact that B lymphocytes and plasma cells do not appear in children may be related to the absence of a gingival pocket. The conversion from a pre-dominantly T- to a predominantly B-cell lesion can be achieved by mechanically ulcerating the wall of the gingival sulcus such as by placement of metal orthodontic bands subgingivally. Structural differences in the gingival tissues may result in differences in susceptibility between adults and children.
- Data supports the idea that at certain sites in some animals and at all sites in a minority of animals, gingivitis does not progress to periodontitis.
- Progression of attachment loss through episodic bursts of activity, frequently in the absence of clinical manifestations of gingivitis, has now been documented to occur in humans
- Data supports that the microflora sequential events in gingivitis are not site-specific
- Gingivitis is a “real” disease, because there is a deviation from, or interruption in, the normal structure or function.
BL:Gingivitis is a disease, (transient or persistent but not progressive), caused by microbial plaque substances. It occurs in bursts and stages (Page & Schroeder, 1976). Migration of PMNs is the prime defense mechanism; the epithelial barrier is the second. The plaque microbiology changes with time. Gingivitis can progress to Periodontitis, but the latter can be established without presence of clinical gingivitis. Dissociation between gingivitis and Periodontitis has been shown. Gingivitis in children is different from adults: few B-lymphocytes and plasma cells and little exudate and neutrophils. Gingivitis is a dynamic and reversible disease.
Progression from gingivitis.
Title:Discussion: Conversion of stable established gingivitis in the dog into destructive periodontitis..
Source: Arch. Oral. Biol. 20:775-782, 1975.
Type: Experimental study
Keywords: Pathogenesis, periodontitis
Purpose:To examine the experimental gingivitis model from established gingivitis to progressive periodontitis in beagle dogs.
Methods:3 beagle dogs. Preparatory period of 2 months, where all teeth of dogs were scaled and polished and brushed 2x/day. At start of study at day 0, amalgam markers were placed in the buccal teeth surfaces above the gingival margin. GI and measurements of exudate were taken. All tooth-cleaning procedures were terminated, the animals were put on a soft diet regimen and microbial plaque was allowed to accumulate freely. Dogs were examined at 1, 2, 4, 12, 18, 21, and 36 months assessing plaque, calculus, PD and AL. At 36 months cotton floss ligatures were placed around the crowns of the lower right 4thPM and left for 5 months, then block sections taken from both the 3rdand 4th PMs.
- 1-36 months clinically showed a rapid plaque accumulation, followed by slower calculus formation, with an increase in GI, exudate and PD.
- After ligature placement, calculus and GI did not increase, but exudate did gradually increase. PD and AL at buccal of 4thpremolar also increased drastically between months 36 and 41.
- Ligated samples exhibited a plasma cell dominated advanced lesion.
- Theproportion between all lymphocyte:plasma cells was consistently about 1:1 in infiltrates of non-ligated but 1:2 in ligated teeth.
- Non-ligated samples showed lymphocyte plasma ratio that resembles an intermediate between the early and the established lesion (Page and Schroeder, 1975).
Conclusion:The advanced lesion is predominated by plasma cells. Chronic gingivitis has equal amount of lymphocyte and plasma cells and is an intermediate lesion b/w early and established type of lesion. The data demonstrated that major phase of tissues destruction probably occurred w/in 1st 4 weeks after ligature placement.
Topic: Progression of gingivitis
Title:The progression of gingivitis to periodontitis in the beagle dog. A histologic and morphometric investigation.
Source: J. Periodontol. 47:435-439, 1976.
Type: Animal study
Purpose:T o determine the pathway of the spread of inflammatory infiltrate in the progression of gingivitis to early periodontitis in Beagle dogs.
Methods:Took M-D & B-L sections of 25 beagle dog jaws with varying degrees of naturally occurring gingivitis and periodontitis; then evaluated the progression of gingivitis to periodontitis.
Results: Spread of inflammatory cell infiltrate follows blood vessels; in both B-L & M-D sections, the inflammatory cells infiltrate into the supra-alveolar connective tissue occurred before any loss of connective tissue to the root surface. In B-L sections, the spread of cell infiltrate passed apicolaterally through the supra-alveolar connective tissue towards the periosteal surface. In the M-D sections, cell infiltrate spread from beneath adjacent teeth surfaces towards the interdental septa; bone resorption B-L progressed from the periosteal surface and within marrow spaces, towards the root surface. Bone resorption IP occurred along the crest of the interdental septa and within marrow spaces; if septum is narrow, horizontal loss occurred, whereas if the septum is wide, vertical bone loss.
Conclusion:Spread of inflammatory cell infiltrate follows blood vessels; the path of spread and pattern of bone loss in periodontitis may be modified by local anatomy.
The formation of periodontal pockets.
How do periodontal pockets form? Which tissues are destroyed first?
Title:The Periodontal Pocket
Source:Journal of Periodontology, October 1952, Vol. 23, No. 4, Pages 199-213
Purpose: To review the histopathology of the periodontal pocket.
Method:Series of mesio-distal sections of a healthy 50-year-old white male. The gingiva was firm, pink and well stippled.
Results:Microscopic anatomy: The stratified squamous epithelium of the pocket is non-keratinized and varies in thickness. Epithelial ridges are elongated and irregular. Close to the bottom of the pocket PMNs can be observed invading the epithelium. The cementum above the bottom of an untreated pocket is always acellular and usually covered with a cuticle produced by the epithelial attachment. This cementum may be considered “necrotic”. Only apical to the base of the pocket evidence of vitality in cementum can be seen. Calculus and materia alba are common findings. The most characteristic feature identifying the bottom of the pocket are the dental cuticle and the rough inner surface of the pocket epithelium. Pockets depth in these specimen varied from 0.4 to 3.1mm. The length of epithelial attachment varies from 0.4-1.7mm. The CT below the bottom of the pocket is seen to be the site of a chronic inflammatory reaction which extends to and beyond the crest of the alveolar bone and is limited by the fiber bundles in some specimens. In other with dense inflammatory infiltration the fiber bundles have completely disappeared. Inflammation extends in the bone marrow spaces and PDL. Distance from the bottom of the pocket to the alveolar crest is 1.3-3.8mm. Alveolar bone shows areas of arrested resorption and new bone formation. When inflammatory cells are seen in the PDL, they are either in areas where the alveolar bone has been largely destroyed or in an area made accessible by a branch of the nutrient canal.
Conclusion:1) In periodontal therapy every effort should be made towards developing procedures that would assure pocket elimination accompanied by an increase in the length of the clinical root.
2) Gingivectomy may be needed after calculus removal and root planning with or without curettage of the soft tissues.
3) The removal of the inflamed CT below the bottom of the pocket is an unwarranted sacrifice.
4) The bone forming the alveolar crest is vital
5) Interference with the epithelial attachment involves a very real surgical risk.
6) Complete pocket elimination with preservation of the existing epithelial attachment and all supporting CT can be accurately and safely accomplished by gingivectomy.
Title: The mechanism of pocket formation – A light microscopic study of undecalcified human material.
Source: J. Periodontol. 59:215-221, 1988.
Type:Histological cadaver study
Keywords:periodontal pocket, formation, periodontitis formation
Purpose: To investigate human periodontal tissues in different stages of pathogenesis using the “sawing and grinding” technique, to provide hard and soft tissue information on the mechanism of pocket formation.
Materials and methods:
- 218 human teeth were excised in block sections from cadavers, cut into 2-3 mm slices, in the mesiodistal direction parallel to the long axis of the tooth. Observed under the light microscope.
- Specimens found consisted of 30 early, 133 established, and 214 advanced lesions according to Page and Schroeder. No initial lesions.
- Pocket formation was initiated by degenerative changes in the second or third cell layers from the innermost cells in the most coronal part of the JE.
- An intraepithelial cleft was formed, followed by degeneration and desquamation of the cells lining the cleft. This resulted in a deep crevice and pocket formation. The disruption of the epithelial barrier along with the concomitant penetration of bacteria and their toxic products was most important to convert an established lesion into an aggressive lesion.
|Amount of plaque||Gingival CT||Extent of inflammation||Epithelial changes|
|Early||Small||Lymphoid infiltration||Sulcular, junctional epithelium||No prominent proliferation of rete ridges|
|Established||Considerable||Plasma cells||Transseptal fiber||Rete pegs extended to CT|
|Advanced||Large||Plasma cells||Alveolar bone||Thin, detached, ulcerated|
Conclusion: Epithelial ulceration was the most remarkable and constant change observed in relation to conversion of established to advanced lesion. With alteration of the highly permeable junctional epithelial barrier, the bacteria and the products easily invade the gingival CT. These findings support the concept that pocket formation is provoked by the effects of the bacterial plaque and the split of the JE from its attachment of the tooth surface.
Title:Scanning electron microscopy of the gingival wall of deep periodontal pockets in humans.
Source:Journal of periodontal research, 17(3), 284-293. DOI: 10.1111/j.1600-0765.1982.tb01155.x
Keywords:electron microscopy, leukocytes-bacteria interaction, bacterial plaque
P: To study the features of the soft tissue wall in deep periodontal pockets in humans with a SEM.
M&M:8 teeth from 6 pts with advanced periodontal disease (PD > 7mm) were extracted together with the pocket tissue (a rectangle of tissue including the bottom of the pocket). No abx taken in past 2 months. Two gingival biopsies from pts with clinically healthy gingiva were also studied for comparison. Specimens of CT and pocket epithelium were viewed under scanning electron microscope. Description of cell types and tissue structures was made on the basis of cell types and sizes, types of cell surface and topographical distribution, and relationships with other cells.
R:Seven topographical areas of the test group were described: areas of epithelial desquamation, leukocyte-bacteria interaction (leukocytes emerging into pocket wall, phagocytosis), emergence of leukocytes (periphery of leukocyte-bacteria interaction), bacterial accumulation (depressions on epithelial surface with abundant debris and fibrin-like material), relative quiescence (epithelial cells with occasional shedding of cells), hemorrhage, and ulceration (occasionally found, and surrounded by areas of hemorrhage) were observed. Bacterial plaque (cocci, rods, filaments with few spirochetes) was seen penetrating into the enlarged intercellular spaces of the pocket epithelium.
The control group (gingival sulcus) displayed a very smooth surface, with barely visible intercellular boundaries, scattered semi-folded desquamating cells, and few isolated bacteria.
D:The presence of different areas may also suggest the theory that periods of quiescence or exacerbation within a pocket may be the cumulative effect of all the activities within the pocket wall.
BL:There are seven different topographical regions in perio pockets, which differ, significantly from a healthy sulcus.
Enzymes implicated in periodontal destruction.
Title:Mechanisms of connective tissue matrix destruction in periodontitis
Source:Periodontol 2000. 1997 Jun;14:144-57.
Keywords:Periodontology, immunology, matrix metalloproteinase,
- Metalloproteinases can be synthesized mainly by connective tissue cells, but also by hematopoietic cells, including monocytes and macrophages, keratinocytes, endothelial cells and many types of tumors.
- They can synergistically digest all the macromolecules of tissue matrices, and depending on their substrates MMPs are divided in 6 groups: collagenases, gelatinases, stromelysins, matrilysin, metalloelastase, and membrane-type.
- MMPs are secreted in latent preforms and are activated near or at cell surface (two pathways) or away from it if appropriate proteolytic activity is available.
One pathway involves the generation of the serine proteinase plasmin from plasminogen; Plasmin can activate most prometalloproteinases.
The second pathway involves membrane-bound metalloproteinases that act on certain promelloproteinases
- Tissue inhibitors of MMPs family are the main inhibitors of MMPs, and the sequences of four of them (TIMP-1 – TIMP-4) are known so far.
- Expression of MMPs and their inhibitors by connective tissue cells is regulated by complex interactions among cytokines, growth factors and hormones.
- Many factors are the products of monocytes and macrophages, and their production in inflammatory situations is a key step in initiating metalloproteinase synthesis and tissue degradation.
- IL-1 seems to be particularly important in upregulation of MMPs, while, the role of TNF, PGs, IL-10, TGF- has also been documented. Fibronectin and fibronectin fragments may also modulate their expression, but this is under investigation.
- The normal turnover of collagen in the PDL may take place largely by intracellular pathway. Tissue destruction in periodontitis results from an imbalance between MMPs and their inhibitors. After plaque accumulation monocytes are activated and produce large amounts of cytokines. These bring the loss of ligament attachment by stimulation of MMPs and osteoclastic activity.
- In more recent work, we could demonstrate the increased release of IL-land tumor necrosis factor –alpha by cultured peripheral blood mononuclear cells from patients with chronic periodontal disease, compared with controls.
- Together with the control of bacteria, drugs that inhibit MMPs action could help in preventing tissue destruction in periodontitis. So far only tetracyclines analogues, such as doxycycline, are used to this direction.
|Classes and properties of human matrix metalloproteinases|
|Group||MMP numbering/other names|
|Collagenases||MMP-1 fibroblast; CL1MMP-8 neutrophil; CL2
|Gelatinases(type IV collagenases)||MMP-2 GLAMMP-9 GLB|
|Stromelysins||MMP-3 stomelysin;transin; SLI
|Membrane-type||MMP-14 MT1 MMP|
Title:Cytokines modulate routes of collagen breakdown
Source:J Clin Periodontol 1997; 24: 297-305
Keywords:burst hypothesis, collagen, collagenase, cytokines, growth factors, metalloproteinase, phagocytosis, periodontitis, wound healing, EGF, IL-1a, TGF-b
Purpose: to review recent work on collagen degradation.
The periodontal ligament has the fastest turnover of colllagenous proteins. The metabolism of collagens in the PDL has to have a precise balance between synthesis and degradation of collagen. Breakdown of collagenous proteins occurs via 2 pathways:
1) Intracellular Pathway
-Under non-pathological conditions, phagocytosis and intracellular digestion of collagen fibrils is observed in connective tissues, such as gingiva and periodontal ligament.
-This pathway may be responsible for all collagen breakdown during normal turnover and considered as primary route of collagen degradation in soft connective tissue.
–Fibroblast is the the main cell involved in this process.
-Cytokines may modulate the intracellular pathway: TGF- β enhance collagen phagocytosis while IL-1α inhibits it. In combination these cytokines antagonize each other.
2) Extracellular Pathway
-In pathologic situations, microbial products may trigger a host response which induces the production and release of cytokines and proteolytic enzymes by inflammatory and resident cells.
-Under such pathological conditions a different pathway for collagen degradation may occur : a metalloproteinase-mediated extracellular digestion.
– MMP-1, or interstitial collagenase: Unique capacity to cleave collagen type I and III.
-The action of collagenase is controled at least at 3 distinct levels involving production, activation and inhibition: First, the enzyme is synthesized and secreted in the extracellular enviroment in an inactive proform (Procollagenase) Second, the enzymes are activated for instance by autoactivation, by MMP-3 or plasmin. Once activated, the enzyme performs its catalytic activity and is subsequently inhibited by specific tissue inhibitors of metalloproteinases (TIMPs)
-The production of collagenase, activators and inhibitors is mediated by a variety of compounds like EGD, FGF, PDGF, TGF- β, TNF- α and IL-1
-The modulation by cytokines of the cascade of Proenzyme-activator-enzyme-inhibitor is likely to have a high relevance in processes like wound healing, chronic inflammatory diseases like perio disease, rheumatoid arthrtitis and tumor invasion.
Collagenase and periodontal disease
-Collagenase found in periodontitis is derived from the host and not from perio-pathogenic bacteria
-2 distinct types of collagenases have been described: 57/52 kD (MMP-1) and 75kD (MMP-8)
|-Derived mostly by fibroblasts-Detected in inflamed but no in healthy periodontal tissues
-Most MMP-1 remains in the gingival tissue during inflammation
|-Derived from nuetrophils where it is stored intracellulalry in granules-Detected in high levels in GCF in gingivitis or periodontitis, but in health it is undetectable
-Majority of released MMP-8 finds its way to the pocket
Cytokine mediate collagenase production
-During periodontal disease cytokines appear to play a crucial role in the regulation of MMP- mediated collagen degradation.
-IL-1 induces proMMP-1 production.
-TGF-b: Cytokine known for wound healing and repair- stimulationg activities. It has a downregulating effect on MMP-1 production and release. It also appear to stimulate the production of TIMP.
Cytokine-induced reservoir of latent collagnase in extracellular matrix: a possible mechanism for a “burst” of periodontal breakdown
-Studies suggest that periodontitis has a cyclic behavior characterized by periods of exacerbation and remission
-Periods of progressive loss involve significant proteolysis during short time-interval. Such a protrolytic burst can be explained by an increase in the synthesis and /or release of enzymes (MMP-1/MMP-8).
-Recent studies have shown that procollagenase, can be stored as a reservoir in the extracellular matrix with a high potential of proteolysis following activation.
-During periods of remission a balance is reintroduced for instance by TIMPs.
-When the chronic inflamatory reaction takes over again, the reservoic of proenzymes is released and another burst ocurs.
Conclusion:Under physiologically stable conditions, collagen is broken down primarily via the intracellular pathway. Under pathological condition(inflammation) cytokines like IL-1 α are released which may induce the production and release of collagenolytic enzymes and also are likely to inhibit the phagocytosis of collagen. Following the release of procollagenase, a substantial fraction of the proenzyme is incorporated into the extracellular matrix. During inflammatory conditions, such a reservoir of latent enzyme could be activated, leading to a sudden and extensive breakdown of collagen. TGF-b may counterbalance these effects during phases of remission or healing, and may contribute to restoraiton of a state of equilibirum.
Title:Evidence of a direct relationship between neutrophil collagenase activity and periodontal tissue destruction in vivo: Role of active enzyme in human periodontitis
Source:J Periodont Res 1995; 30:23-33
Keywords:collagenase, collagen degradation, neutrophil, periodontitis
Purpose:To assess the temporal relationship between periodontal tissue destruction and the activity of collagenase.
Method:Subjects were classified into three groups (at least 14 per group)
Group 1– Progressive periodontitis– Previous surgical treatment for perio in the last 5 years and on the basis of clinical charts, or 2 mm of attachment loss.
Group 2- Stable periodontitis– No detectable loss of attachment >2 mm within the last 3 years
Group 3- Gingival inflammation with no attachment loss– No history of attachment loss and no periodontal treatment
Groups 1 and 2 received periodontal treatment to create a baseline while group 3 did not. Subjects were examined monthly (PD and BOP). GCF was also collected at each exam and latent/active collagenase activity was analyzed via SDS-PAGE and fluorography.
Results:A total of 58 subjects were enrolled and 1981 sites were sampled and analyzed. Crevicular fluid flow was high in all groups but lowest in group 3. Group 1 subjects exhibited a higher increase of active collagenase activity with time. Group 2 had no significant increase in activity over time. Latent enzyme did not increase in any group and was highest in group 3
Conclusion:Active collagenase, but not latent collagenase, in an inflammatory exudate is temporally linked to net tissue destruction. If the degradative mechanisms in periodontal diseases are common with other inflammatory CT diseases, then understanding of the activation mechanisms of the proenzyme could provide novel approaches to therapeutic control of these diseases.
Title:Mechanisms of alveolar bone destruction in periodontitis
Source: Periodontology 2000, Vol. 14, 1997, 158.1 72
Reviewon alveolar bone destruction in periodontal disease
DISC:Bone is a metabolically active organ composed of both mineral and organic phases that is designed for its role as the load-bearing structure of the body. It is formed from a combination of dense, compact bone and cancellous bone that is reinforced at points of stress.
Cortical bone is made up of the Haversian system which is found around central blood vessels. Spatially the cells in the Haversian system cover a relatively small surface area. In contrast cells in cancellous bone occupy a large portion of the surface. This observation may explain why cortical bone exhibits lower metabolic activity than cancellous bone.
Cortical bone is confined by the periosteum on the outside and the endosteum on the inside. Periosteum is important for bone modeling during growth. Modeling is the process used by bone to shape itself.
Two major cell types:
1) osteoblast– synthetize organic matric components and direct the events resulting in mineralization. Once the osteoblast is surrounded by a mineralized matrix, it is termed an osteocyte
2)osteoclast- resorb both the mineral and organic phases of the bone.
Bone is constantly undergoing the process of remodeling. The bone is constantly resorbed on a particular surface, followed by a phase of bone formation. In normal adults, there is a balance between the amount of bone resorbed by osteoclasts and the amount of bone formed by osteoblasts.
During resorption the osteoclasts release local factors from the bone. These factors have two effects: inhibition of osteoclastic activity and stimulation of osteoblast activity. Osteoclasts produce and release factors that have a negative regulatory effect on themselves and enhance osteoblast function. When osteoclasts complete the resorptive process they secrete proteins that later serve as a substrate for osteoblast attachment. The active osteoblasts also produce local factors, enhancing autocrine regulation.
–Factors that regulate bone resorption
- IL-1– potent bone resorbing cytokine, direct stimulation on osteoclasts, and stimulate the production and release of prostaglandin, which stimulate bone resorption. IL-1 also stimulates the proliferation of cells at early stages of differentiation into osteoblasts.
- IL-6– In some experimental models, IL-6 appears to have no effects on bone resorption, but in others it stimulates bone resorption. IL-6 is also responsible for the formation of cells with an osteoclastic phenotype. Osteoblasts can also produce IL-6. The amount produced is increased in response to cytokines and hormones .
- TNFa– produced by activated lymphocytes – major effect is to stimulate osteoclastic bone resorption. It has been suggested that part of the effect of TNFa is mediated by PGE2 and IL-6.
- Gamma Interferon – works opposite to TNFa and IL-1, effective in inhibiting bone resorption induced by IL-1 or TNFa
- Colony Stimulating factors – can stimulate IL-1 production and prostaglandin synthesis – leading to osteoclast formation
- Prostaglandins– prostaglandins of the E series are slow-acting but powerful mediators of bone resorption and affect both active mature osteoclasts as well as differentiated osteoclast precursors. In vitro it has been found that in high doses are inhibitory, and in low doses stimulate bone formation
- Sex steroids– androgens probably affect osteoclastic bone resorption
–Factors regulating bone formation:
- PDGF– 3 isoforms exist: AA, AB and BB. The most biologically active form in skeletal tissue is BB. It is produced by osteoblasts, serum and platelets. Stimulate DNA synthesis and cell replication in osteoblasts, increase bone collagen synthesis and rate of bone apposition. PDGF-BB might be critical in wound healing or fracture repair since it is released after platelet aggregation.
- Heparin binding GF – shown to be mitogenic for bone cells and to enhance collagen and non-collagen protein synthesis
- Insulin like Growth Factor –
Insulin like growth factor I – termed somatomedin C
Insulin like growth factor II- termed multiplication stimulating activity
– increase preosteoblastic cell replication and have a stimulatory effect on osteoblastic collagen synthesis and bone matrix apposition. Also shown to decrease the degradation of collagen
- Transforming Growth Factor B – stimulate preosteoblastic cell replication, osteoblastic collagen synthesis, bone matrix apposition and alkaline phosphatase activity
- BMP– induces the endochondral pathway by inducing chondrocyte differentiation and matrix mineralization, stimulate the differentiation of osteoblasts and collagen production
Summary of Bone destruction – Plaque and its associated bacteria which populate the periodontal pocket, release LPS and other bacterial products into the sulcus, affecting both the immune cells in the connective tissue, as well as the osteoblasts. In the immune cells, these products induce local factor production, including IL-1a, IL-1b, IL6, prostaglandin, and TNFa. These factors increase osteoclast formation and activation as well as inhibit osteoblast function. The bacterial products will also affect the osteoblast directly, inhibiting their function and inducing factor production and release, eventually inducing pre-osteoclast differentiation and osteoblast activation.
Title:Differential Expression of RANKL and Osteoprotegerin in Gingival Crevicular Fluid of Patients with periodontitis.
Source: J DENT RES 2004 83: 166
Type: Clinical study
Keywords: Pathogenesis, periodontitis
BG:Osteoclast formation and activation requires the receptor activation of NF-kB ligand (RANKL). Osteoprotegrin is a secreted glycoprotein that is a decoy receptor for RANKL, so that when OPG binds to RANKL, osteoclast activity is prohibited. A soluble form of RANKL can be secreted by activated T cells and osteoblasts that has been show to increased destruction and inflammation in joints of pts with rheumatoid arthritis.
Purpose:To investigate if the RANKL and osteoprotegerin (OPG) levels in GCF are elevated in patients with periodontitis.
Methods: 132 healthy pts with chronic generalized periodontitis around single rooted teeth, classified as mild (AL<3mm, 27 pts) , moderate (AL 4-6mm, 58 pts), and severe (AL>7mm, 47 pts). Control group had 28 pts with PD <2 and no AL, no BOP, no radiographic bone loss. GCF samples from 2 diseased sites and healthy controls. All clinically detectable supragingival plaque was carefully removed without touching gingiva and teeth were gently washed with water. One paper strip was used for each collection site, as they were inserted 1mm into gingival crevice and left there for 30 seconds. The volume of GCF in the paper strips was measured with a Periotron. The paper strips for each participant were pooled, and
the GCF was extracted and assayed for the content of RANKL and OPG. GCF was extracted from the paper strips with buffer and collected following centrifugation. ELISA test was run to analyze levels of RANKL and OPG.
- RANKL in GCF of controls was below detectable limit in 96% of pts (27/28 ).
- Concentrations of RANKL in GCF SS higher in pts with periodontitis than in healthy controls. SSD between mild and moderate or severe in terms of RANKL concentration (more in moderate).
- OPG levels in periodontitis patient were SS lower than controls, but were not associated with clinical severity OPG in the GCF decreased as disease severity increased.
- A calculated ratio of RANKL:OPG was SS higher for patients with any degree of periodontitis than in controls. The patients with mild periodontitis had a higher concentration of RANKL in their GCF than those with moderate or severe periodontitis
Conclusion:Pts with periodontitis had a SS increase in RANKL and SS decrease in OPG levels of the GCF when compared to controls. This would indicate that RANKL is an important mediator of bone destruction whereas OPG can have a protective function.
Title: Effect of Age on Gingival Crevicular Fluid Concentrations of MIF and PGE2
Source:J DENT RES 2009 88: 639
Keywords:age, experimental gingivitis, PGE2, MIF, real-time PCR
Purpose:To evaluate the difference in Migration inhibitory factor (MIF), and PGE2, in young and old patients with and without gingivitis, and also evaluate microbial constituents of plaque.
Methods: Experimental gingivitis (cessation of OH for 2wks) on younger adults (18-30 years old) and older adults (46-77 years old). Participants received professional tooth cleaning and OHI over a period of 3 weeks. At baseline, clinical data were recorded, and subgingival samples were collected for immunological and microbiological analysis, using ELISA and PCR respectively. No oral hygiene for 2 weeks. Examinations were repeated on days 8 and 15.
Results:No differences in clinical parameters between different age groups at any period of the experiment, although slightly higher plaque index in older patients. All showed higher plaque, gingival indices and bleeding on probing. PGE2 increased in younger participants between 1 and 2 weeks, whereas it decreased in older individuals over the same period. An inverse significant association was observed between PGE2 concentration (decreased) and plaque index (increased) in the older age group, no significant associations were observed between clinical parameters and concentrations of PGE2 in younger patients. Compared to baseline MIF increased in younger patients but showed a decrease over time in older individuals. Older participants had significantly higher counts of Parvimonas micra and P. gingivalis than did younger participants. A tendency toward higher counts of total bacteria(D. pneumosintes and P. intermedia) was observed in the older age group, but did not reach statistical significance. No significant associations were observed between MIF concentration and bacteria counts in younger participants. Older participants, total count of bacteria (P. micra and P. intermedia) was significantly associated with MIF concentration, and a borderline correlation was observed for P. gingivalis, but not enough to account for the differences in the two groups (meaning that MIF differences were more attributed to age rather than to specific bacteria).
|Age group||Level||Clinical parameter association|
|Older||Decreased||Yes – Inverse|
|Age group||Level||Bacterial count association|
Conclusion:MIF and PGE2 production in response to bacterial accumulation seems to be modified by age, and as the immune system ages, the immune responses may decline as well. This was the first study to show MIF in gingival crevicular fluid, the discrepancy in MIF concentration between younger and older population could support the theory that aging may be accompanied by a low-grade chronic up-regulation of inflammatory mediators.
Title:Vascular endothelial growth factors and progression of periodontal diseases.
Source:J Periodontol. 1999 Aug;70(8):848-52.
Keywords:VEGF, periodontal disease
Purpose:To document the concentrations of Vascular Endothelial Growth Factor (VEGF) within normal gingival biopsies and tissues adjacent to three diseased sites.
Method:Gingival papillae were obtained from 52 Hispanic patients prior to routine tooth extraction. 10 samples of healthy gingiva (3mm or less PD, no BOP) and 42 from sites that had BOP with different PDs (16 samples with PD of 3mm or less, 16 between 4-6mm and 10 with 6mm or more) were obtained. Part of the samples was frozen for biochemical analysis and part was prepared for histologic evaluation. Distribution of blood vessels was determined, proteins were determined and ELISA was also used to determine IL-6 or VEGF. Statistical analysis was performed. IL-6 concentrations were determined since it is a recognized progression factor of periodontal disease.
Results:Mean number of blood vessels was lowest within both normal and diseased gingiva with PD 3mm or less, higher in the 4-6mm and highest within gingiva of 6mm or more pocket. Protein concentrations in tissues from the healthy sites were highest and became progressively reduced in diseased tissues coincident to increased vascular depth. IL-6 and VEGF concentrations were lowest within normal tissues significantly higher in diseased tissues. VEGF and VEGF/IL-6 ratio was higher in the 4-6mm category. IL-6 concentrations were correlated with PD but not VEGF concentrations.
Conclusion:VEGF is likely a factor in the etiology of gingivitis and its progression to periodontitis, possibly by initiating expansion of the vascular network.
Modulation of the host response.
Topic:Review of Host Modulation
Title: Host response modulation in the management of periodontal diseases.
Source: J Clin Peridontol 2005; 32 (Suppl. 6): 108–129.
Keywords:cytokines; gingivitis; host modulation; inflammation; periodontitis; prostaglandins
Purpose: To review the biological mechanism and clinical utility of therapeutic modulation of the host response in the management of periodontal diseases.
Materials and methods:
- MEDLINE-PubMed search was performed up to Dec. 2004 and limited to in-vitro, experimental, and clinical studies published in English. All levels of evidence included: systematic reviews, randomized-controlled clinical studies and case reports of human and experimental animal studies.
Discussion of different host-modulating agents. Six chemotherapeutic agents identified:
- NSAIDSare weak organic acids that selectively (COX-2) and non-selectively (COX-1) inhibit the synthesis of arachidonic acid metabolites blocking production of prostaglandins, thromboxanes, and prostacyclines, slowing periodontal disease progression. Good clinical results, but serious adverse side effects (gastric ulcerations) have limited their use as an adjunct to periodontal treatment.
- Lipoxins (lipid derived mediators) are capable of preventing gingival inflammation and bone loss. Suggested that these molecules are unique counter-regulators to inflammatory responses. Studies only done in animal experimental periodontal disease shows that lipoxins are capable of preventing gingival inflammation and bone loss.
- Tetracycline (TTC) and doxycycline (SDD) inhibit MMPs. 20mg 2X/day of doxycycline in clinical studies has been shown to decrease collagenase activity without the emergence of doxycycline resistant microorganisms. Studies ranged from 9-24 months showed a significant reduction of MMP’s in gingival crevicular fluid.
- Bisphosphonates- modulate bone remodeling. Only animal studies. Shown to decrease MMPs and decreased bone loss in periodontitis induced sites.
- Cytokine antagonists, like IL-1 receptor antagonist and soluble TNF-a receptors can competitively inhibit receptor mediated signal transduction. Only animal and experimental studies.
- Inhibiters of nitric oxide synthase activity (NOS), a highly reactive free radical that leads to lipid peroxidation, protein and DNA damage, and stimulation of cytokine release. Only have animal studies shows reduction in periodontal attachment loss and bone loss.
Title:New directions in host modulation for the management of periodontal disease
Source:J Clin Periodontol 2009; 36: 124–126 doi: 10.1111/j.1600-051X.2008.01354.x
Keywords:anti-inflammatory, drug discovery, inflammation, periodontitis, resolution
P: To comment about periodontal disease in light of a new understanding of the role of inflammation in disease expression, thus setting the stage for the development of new prevention and treatment strategies.
· Approach to periodontal disease has changed, from blocking inflammation to moderating it.
· Endogenous molecules resolving E1 (RvE1) and protectin D1, play the role of resolution antagonists, as acute inflammation undergoes an active process of resolution.
· Van Dyke (2007) propose that by introducing resolving agents, perhaps the resolution of inflammation leads to disappearance of the pathogenic bacteria by removal of their food source.
. Therapeutic manipulation of fibroblasts (Flavell et al. 2008) and their biologically active products is an emerging concept in treating cancer and is likely to provide a novel method to achieve improved control of chronic inflammatory disease, with possible applications in the field of periodontitis.
· By using drugs that promote resolution rather than just anti-inflammation, we may be able to harness the advantages of the inflammatory cascade.
· RvE1 (tested in animals) has been shown to markedly reduce periodontal inflammation with regeneration of bone to pre-ligature height, regeneration of cementum and organized PDL.
· A set of resolution indices has been proposed to assess the impact of pro-resolving agents.
· If pro-resolving agents continue to be developed, then clinical changes will need to be made in how we differentiate the signs of inflammation from those of resolution.
· We are not aware of many commercially available drugs that utilize the resolution pathway.
BL: The emerging awareness of the control of inflammation in periodontal disease management underscores the importance of exploring inflammatory pathways and mediators and thus better understanding possible new interventions.
Steven J. Spindler, DDS, LLC updated 2020.7.8 sjs