Biochemical Approach to Dental Disease

7/30/2019 Biochemical Approach to Dental Disease

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CLINICAL DENTISTRY AND RESEARCH 2011; 35(1): 57-64

Correspondence

Yasemin Aksoy, MD

Department of Medical Biochemistry

Faculty of Medicine

Hacettepe University

06100, Shhiye, Ankara, Turkey

Phone: +90 312 3051652/125

Fax: +90 312 3245885

E-mail:[email protected]

Yasemin Aksoy, MDAssociate Professor, Department of Medical Biochemistry

Faculty of Medicine, Hacettepe University, Ankara, Turkey

INVITED REVIEW

BIOCHEMICAL APPROACH TO DENTAL DISEASES

ABSTRACT

The major change in the biochemical constituents of the

connective tissue during dental diseases especially during

pulpitis, gingivitis and periodontitis is the loss of collagens due

to degradation. There are at least four dierent mechanisms by

which the extracellular matrix can be degraded. These include

the release of enzymes by host and bacterial cells, phagocytosis

of matrix components, release of reactive oxygen species and

the release of a wide range of cytokines, inammatory mediators

and apoptotic proteins that inuence enzymes connected with

matrix components. The elevated levels of these molecules

and enzymes ultimately reect the degree of the dental

inammations, as a result signifying that the host derived

molecules can take part in the progression of periodontal and

peri-implant inammatory diseases. Researchers studying the

proteins involved in cell defense system will have the chance of

directing treatment.

Key words:Antioxidant Enzymes, Cytokines, Inammation,

Matrix Degradation, Oral Diseases, Oxidative Stres.

Submitted for Publication:11.29.2010Accepted for Publication :12.06.2010

INFLAMMATION AND ITS CONSEQUENCES

Inammation and oxidative stress have become major health

issues in current years, the subject of many researches.

Inammation is bodys natural reaction to invasion by an

infectious agent, toxin or physical, chemical or traumatic

damage. There are some inammatory situations in dental

diseases; their names are pulpitis, gingivitis, periodontitis etc.

Inammatory process is often associated with free radical

damage and oxidative stress. The sources of free radicals

are both external (chemicals, drugs, tobacco, electronic

pollution, stresses of all kinds) and internal (mitochondrialrespiration). If body is unable to stop the amplication free

radical chain reaction, oxidative stress results. Oxidative

stress damages cellular proteins, membranes and genes and

leads to systemic inammation.

Oxidative stress and inammation biomarkers, as well

as anti-oxidants and anti-inammatory factors, need to

be measured concurrently. This is due to the fact that


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CLINICAL DENTISTRY AND RESEARCH

Figure 1. Mechanisms through which toxins may aect wound healing.

Toxins-induced production of ROS, TNF can have direct eects on

repair that include the inhibition of collagen production by osteoblasts

or broblasts derived from the gingiva . However, they could also have

profound indirect eects by promoting inammation or, potentially,

through enhanced apoptosis (modied from 1)

metabolic processes overlap and the lack of balance

between these stressors and protectors may guide to

development of oral diseases. The formation of reactive

oxygen species (ROS), tumor necrosis factor (TNF) could

potentially aect oral healing or the response to bacteria

induced periodontitis, by direct eects on osteoblastic or

broblastic cells, such as reduced expression of collagen, or

indirectly through promoting inammation and apoptosis of

these matrix-producing cells (Figure 1). Thus, by enhancing

the production of ROS, TNF, toxins may impair the healing

response or progression of dental disease.1

There are many biomarkers of inammation and oxidative

stress. This review presents the role of oxidative stress and

inammation in the tissue destruction and explains the

biochemical markers during these processes.

OXIDATIVE STRESS AND ANTIOXIDANT SYSTEM

In recent years, investigations have linked oxidative stress

with the pathophysiology of dental tissues. Oxidative

stress characterized by an increased level of reactive

oxygen species (ROS) that disrupts the intracellular

reduction-oxidation balance. Actuality, depending on their

concentration, ROS can either have benecial or deleterious

eects on mineralized tissues. ROS are mainly represented

by the superoxide radical (O2

.-), hydroxy radical (.OH) and nitric

oxide radical (NO.) species, and non-radical derivatives of

oxygen, such as hydrogen peroxide (H2O

2) and hypochlorous

acid (HOCl).2 The presence of unpaired electrons in the

outer orbitals of oxygen derived free radicals makes such

species, especially the .OH species, extremely reactive in

nature.3,4 ROS are produced in cells at various sites including

plasma membrane, mitochondria, endoplasmic reticulum and

cytoplasm.

Polymorphonuclear leukocytes (PMN) are widely believed

to be the initial and predominant defense cell produced

during the host response against bacterial pathogens in a

variety of pathological conditions including inammatory

dental diseases. Several enzymatic complexes are

responsible for ROS production, including NADPHoxidase, cytochrome P450, xanthine oxidase, monoamine

oxidase, cyclo-oxygenase and lipoxygenase. Following

stimulation by bacterial antigen, PMN produce O2

.- via the

metabolic pathway of the respiratory burst catalyzed

by NADPH oxidase, during phagocytosis. O2

.- is released

into the phagosomal space and also into the extracellular

environment. In addition, NO is produced by macrophages via

nitric oxide synthase during acute inammation by vascular

endothelium. The non-radical species, HOCl, is also a potent

antimicrobial agent and is generated by azurophilic enzyme

myeloperoxidase (MPO), during phagocytic degranulation.The production of HOCl has been shown to have a positive

correlation with periodontal diseases.5 Data regarding

gingival crevicular uid myeloperoxidase and elastase-like

activity present periodontal disease and health status. MPO

activity in gingival tissue displayed a signicant increase in

patients with periodontal disease when compared with the

control group.6-9 Tissues may be exposed to a variety of free

radicals during inammatory reactions. Especially where

PMN and macrophages are in abundance and respond with

signicant quantities of oxygen derived free radicals, which

may cause signicant cellular and tissue damage. Theeects of free radicals on cells and tissues are many and

varied. These include disruption to cellular proteins, nucleic

acids and plasma lipids as well as causing de-polymerization

of matrix components such as collagen, hyaluronan and

proteoglycans. In addition to free radicals, cytokines also

contributes to connective tissue degradation.Those harmful

eects are controlled by enzymatic and non-enzymatic

antioxidant system.


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"BIOCHEMISTRY AND DENTISTRY"

The agents that scavenge reactive species or prevent their

formation should decrease the tissue damage to an extent

related to their antioxidant action in vivo. This means that

their ability to decrease formation of or damage by reactive

species should correlate with their ability to prevent

tissue injury.8 Important antioxidants include; 1) the chain

breaking or scavenging ones like vitamin E (-tocopherol),

vitamin C (ascorbic acid), vitamin A (-carotene), urate, 2)

those substances containing thiol groups-preventative

antioxidants-that function largely proteins by nature

(albumin, transferrin, lactoferrin, ceruloplasmin, ascorbic

acid and glutathione) and 3) enzyme antioxidants that are

enzyme systems that function by catalyzing the oxidation

of other molecules like catalase (CAT), superoxide dismutase

(SOD), glutathione peroxidase (GSH-Px), glutathione

S-transferase (GST), glutathione reductase (GR) (Figure

2).10,11,12These agents acting as scavengers help to prevent

cell and tissue damage that could lead to cellular damage

and disease.

The signicance of antioxidants is under research in clinical

dentistry. During tissue inammation, molecules such as

H2O

2and O

2.- are released from host cells; these oxidizing

agents are able to destroy bacterial components as well as

normal components of the surrounding cells and matrices.

So as to evade excessive tissue destruction, host cells

such as neutrophils release several enzymes that can

degrade these oxidizing agents. There are several studies

on antioxidant enzymes related with dental diseases such

as gingivitis and reversible-irreversible pulpitis. While the

activities of SOD, CAT were increased in reversible pulpitis,

there was a decrease in activities of these enzymes in

irreversible pulpitis and gingivitis when the experimental

and control groups were compared.6,13-16 One probable

rationalization for these responses is that the patients with

oral diseases were in divergent stages of the disease. By the

way, it is well known that the antioxidant responses found

in dierent pathologies rely on the severity or expansion

suered by the patients, and long term chronic conditions

may have jeopardized the antioxidant defenses.17 The

analyses of the enzymes such as GST, GSH-Px, GR revealed

a signicant increase in gingival tissue of individuals with

periodontal disease.18-20 All of these enzymes are related

with reduced glutathione. The ubiquitous tri-peptide

glutathione acts directly as a generic ROS scavenger or

as a cofactor of GSH-Px and GST. The enzyme GR has an

important antioxidant function related to GSH-Px and GST,

GR intervention continuously regenerates GSH from GSSG

in the presence of NADPH, therefore preventing cellular

loss of GSH.20 GSH/GSSG ratio is important for evaluation

oxidative stress degree.21,22 Thats why to assess both of

GSH and GSSG level and GSH related enzymes activities is

signicant for situation of cells. Oxidative damage markers

can measure easily in oral tissues such as pulpa, dentin,

gingiva and oral uids such as gingival crevicular uid, peri-

implant sulcular uid, saliva.

TISSUE DEGRADATION: CYTOKINES-MMP

CONNECTION

Endogenous and exogenous factors activate collagen

degradation. The endogenous factors include a local

variation in membrane thickness and a reduction in collagen

content. The exogenous factors include the eects of

bacterial metabolism and host inammatory response.Infection-induced activation of Matrix Metalloproteinases

(MMPs) has recently been shown to be related with excessive

collagen turnover and membrane weakening, leading to

tissue destruction. MMPs are involved in physiological

process such as tissue development, remodeling and wound

healing. They also play important roles in the regulation of

cellular communication, molecular shedding and immune

functions by processing bioactive molecules including cell

surface receptors, cytokines, hormones, defensins, adhesion

molecules and growth factors.23 Cytokine activation of cells

can lead to increased processing of MMPs from inactivezymogens to the active enzymes. Cytokines and their

receptors can also be substrates for MMP action. Many of

the membrane-bound cytokines, receptors, and adhesion

molecules can be released from the cell surface by the

action of a subset of metalloproteinases called convertases

(Figure 3). 24,25

The toxins, enzymes and metabolites of potent pathogenic

bacteria present in dental plaque are considered to be the

initiating factors of the host immune response which is

primarily responsible for the tissue destruction. It is the host

cells which produce and release pro-inammatory mediators

(cytokines and chemokines) as well as ROS, prostaglandins

and cysteine proteases and matrix metalloproteinases

(MMPs). Lipopolysaccharides (LPS) derived from bacterial

membrane have the capacity to activate host epithelial cells

to express and release pro-inammatory cytokines IL-1, IL-6

and TNF-. It is also important to point out that macrophages

comprise the main source of TNF- in periodontal tissues.26


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Figure 2. Major reactive oxygen species pathways and antioxidant systems. Some of the main pathways in the formation and detoxication of

reactive oxygen species. Abbreviations: GSH, reduced glutathione; GSSG, oxidized glutathione; SOD, superoxide dismutase12

Endogenous and exogenous factors activate collagen

degradation. The endogenous factors include a local

variation in membrane thickness and a reduction in collagen

content. The exogenous factors include the eects of

bacterial metabolism and host inammatory response.

Infection-induced activation of MMPs has recently been

shown to be coupled with excessive collagen turnoverand membrane weakening, leading to tissue damage.

Collagenolytic process is mediated by MMPs, each of

which degrades a type-specic substrate. According to

these substrates, 28 MMPs are identied in vertebrates,

of which 24 are found in humans. MMPs are classied into

six dierent subfamilies; 1) collagenases, 2) gelatinases, 3)

stromelysins, 4) matrilysins, 5) membrane type MMPs, and

6) others.27 Collagenases are the most ecient MMPs to

cleave not only collagens I, II, and III, but other extracellular

matrix (ECM) molecules and proteins as well. The main

substrate of gelatinase subfamily is gelatine, but both

collagenases and gelatinases are capable of digesting a

number of other ECM molecules. MMP-2 (Gelatinase A)

eciently digests collagens I, II, and III in the same manner

as the collagenase subfamily does. Stromelysins digesta number of ECM molecules and participate in pro-MMP

activation.27 MMPs present in oral uids (gingival crevicular

uid-GCF-, peri-implant sulcular uid-PISF-, mouth-rinses

and saliva) can be utilized to develop non-invasive, chair/

bed-side, point-of-care diagnostics for periodontitis and

dental peri-implantitis. MMPs have been suggested to play

an important role in the destruction of dentin organic matrix

following demineralization by bacterial acids and, therefore,


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in the control or progression of carious decay. They may be

activated by an acidic pH brought about by lactate release

from cariogenic bacteria. Just the once activated, they

are able to digest de-mineralized dentin matrix after pH

neutralization by salivary buers.27,28

There are several regulatory mechanisms that can inuencethe ultimate impact of an MMP on ECM degradation.

MMP activity is tightly regulated not only via control

of transcription and translation but also at the post-

translational level (activation of zymogen forms of MMPs)

as well as at the tissue level (by specic regulators known

as the tissue inhibitors of metalloproteinase (TIMPs). In

humans there are four members of the TIMP family.29 The

major function of TIMPs is the inhibition of MMPs, they can

also take part in MMP transportation and stabilization.30,31

It has been recommended that periodontal destruction

is an outcome of the imbalance between MMPs and theirinhibitors.32 Increase in MMP and decrease in TIMP levels

start collagen degradation. MMP-8, also called neutrophil

collagenase-2, is one of the major collagenases that have

a major part in the destruction of connective tissue and

alveolar bone in periodontitis. MMP-8 can be activated by

other MMPs (namely MMP-2, MMP-13, and MMP-14), ROS

and inhibited by TIMP-1 and TIMP-2.32 Abundant information

is available on the role of MMPs in health and disease, but

information on TIMPs is limited, especially with respect to

their role in oral diseases.

Like in other inamed tissues MMPs are present in inamed

dental pulp tissue and periapical lesions.24,33,34 The level of

MMP-8 in periapical exudates decreases during successful

root canal treatment, while in cases with persistent

inammation the levels remain high, indicating that MMP-8

dip-stick analysis from periapical exudate could be used

to monitor inammatory activity and the achievement oftreatment in teeth with periapical lesisons.34

Figure 3. Cytokine activation of cells can lead to increased processing of MMPs from inactive zymogens to the active enzymes. Cytokines and

their receptors can also be substrates for MMP action. Many of the membrane-bound cytokines, and adhesion molecules can be released from the

cell surface by the action.


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The presence and role of dierent MMPs in dentin has

recently been under increasing interest. Dentin MMPs

have been suggested to be involved in caries progression,

degradation of hybrid layer under composite llings and in

pulpal and periapical inammation. The physiological roles

of dentin-embedded MMPs remain unknown, but they have

been speculated to be involved, e.g. in peritubular dentin

formation, mineralized dentin maturation and liberation of

growth factors from dentin during wear and caries. The role of

MMPs in oral diseases still requires basic research to nd the

right combination of MMP inhibitors or possible activators35.

There are series of studies of Professor Sorsa T , Professor

Tjaderhane L and collaborators on MMPs and inhibitors in

oral diseases. In addition to destructive enzymes like MMPs,

it is possible to evaluate tissue breakdown products such

as osteonectin, laminin, tip I collagen peptides for tissue

injury.36 The excessive amount of collagen degradation

products, such as pyridinoline cross linked carboxyterminal

telopeptide of type I collagen (ICTP) in GCF and/or in saliva is

regarded to predict alveolar bone loss in periodontitis.30,37

CELL DEATH

Proteolytic damage by any of the proteases can trigger cell

death, although activation of a protease is not necessarily

identical with apoptosis. However, during proteolysis

of several biologically active intra- and/or extra-cellular

molecules, MMPs can up or down-regulate apoptosis

in a context-dependent manner, in which the relative

concentrations, tissue specicity, and spatiotemporal

balance between MMPs and TIMPs will also inuence

the proteolytic cascade, determining the commitment to

programmed cell death (PCD) .38-40

Apoptosis constitutes an endogenous physiologic

mechanism of cell death, triggered through a diversity of

internal or external. Extracellular signals may include free

radicals, viral infections and bacterial toxins, cytokines,

growth factors, extracellular matrix that inhibit cell death

or endorse cell survival. There are two major pathways,

intrinsic and extrinsic, throughout which apoptotic signals

are transmitted, resulting in activation of caspases.41,42 Many

organelles and molecules are involved in these pathways,

including mitochondria, endoplasmic reticulum, cytochrome

c, death receptors and their corresponding ligands, and

adaptor molecules. Besides these, dierent genes and their

products play a vital role in the control and execution of

apoptosis.43

Apoptosis plays omnipresent role in the body. Amongst other

things, apoptosis is a key process in oral development 44, the

evolution of oral disease45, wound healing46 and in certain

pharmacological eects .The understanding of the ability

of clinical materials to selectively induce or inhibit apoptosis

is leading to new treatment modalities.47 An understanding

of the mechanisms of apoptosis may lead to adjunctive

treatments for pulpal and periradicular diseases through

yet unknown pathways.48 Since the extended presence of

chronic inammatory cells producing osteolytic factors may

be a key stimulator of chronic bone destruction, reduced

lymphocyte apoptosis could be a important factor in the

pathogenesis of periodontal disease. Several studies have

investigated the role of apoptosis in periodontal disease

Bacterial products have been shown to induce apoptosis as

well as prolong the lifespan of inammatory cells.49

CONCLUSION

The accelerated expression of antioxidant and proteolytic

enzymes along with cytokines were associated with the

degree of oral tissue inammation. The elevated levels of

these molecules and enzymes eventually reect the extent

of the dental inammations, thus suggesting that the

host derived molecules can participate in the progression

of periodontal and peri-implant inammatory diseases.

Antioxidant enzymes such as GR, GSH-Px, GST, SOD,

CAT, acting as scavengers help to prevent cell and tissue

damage that could lead to cellular damage and disease. It is

important to evaluate infection-induced activation of MMPs

and MMPs/TIMP ratio. The balance between MMPs and

TIMPs will also inuence the proteolytic cascade, thats why

determining the pro-apoptotic, apoptotic and anti-apoptotic

proteins levels. To determine the degree of inammation

there is a need to assess cytokines, especially TNF, IL-1.

These biomarkers may prove to be diagnostically useful

tools and also targets of medication in the future.

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Biochemical Approach to Dental Disease

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