Bio chemical mediators
INDIAN DENTAL ACADEMY Leader in continuing dental education www.indiandentalacademy.com www.indiandentalacademy.com
INTRODUCTION Histological,histochemical and immunohistochemical studies have elucidated many details of the biological response to orthodontic forces and this acquired knowledge has frequently enabled clinicians to mold their therapeutic approaches to the individual patient’s constraints. Two major responses elicited by orthodontic forces are orthodontic tooth movement brought about by bone and pdl remodeling and pain. Its of advantage to the orthodontist to know the biological events that unfold during tooth movement because it varies from person to person . www.indiandentalacademy.com
PERIODONTAL LIGAMENT Orthodontic tooth movement evokes cellular responses in the pdl and the alveolar bone. Each tooth is attached to and separated from adjacent bone by heavy collagenous fibers called the pdl. Other major constituents of the pdl are the cellular,vascular and neural elements along with the tissue fluids that play a vital role in orthodontic tooth movement. Nerve endings are also found with in the ligament associated with perception of pain and the more complex receptors associated with pressure and positional informationwww.indiandentalacademy.com
Contd‌ Proprioception –mechanoreceptors egs Ruffini and Meissners corpuscles. Principle changes are that of undifferentiated mesenchymal cells and their progeny in the form of fibroblasts and osteoblasts. Undifferentiated mesenchymal cells under tension differentiate into osteoclasts and cementoclasts,these same cells under pressure differentiate into osteoblasts,fibroblasts and cementoblasts. Pdl is a fluid filled chamber with retentive but porous walls cud be a description of a shock absorber along with the pdl space. www.indiandentalacademy.com
GLICKMANN.
BONE Orthodontic tooth movement is brought about by remodeling of the alveolar bone. Bone remodeling is a complex process involving a no. of cellular functions directed towards resorption and formation of new bone. Bone is of two types:1.Cortical bone. 2.Cancellous bone.
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Contd‌ Two principle cell types are osteoblast and osteoclast - major effectors in the turnover of bone matrix. The osteoblast produces a matrix which becomes mineralized in a well regulated manner.The mineralized matrix can be removed by the activity of the osteoclast when activated. Insulin like growth factor-I in response to mechanical forces may act as coupling factor in bone remodeling.BR is regulated by systemic hormones and local factors like cytokines and PGs. Osteoclasts may release paracrine factors,IL-1,IL-6 and annexin-II for osteoclasts recruitment{Roodman,1996} P.A.HILL,BJO 1998,VOL
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osteoblast osteocyte
osteoclast
.
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1,25 Dihydroxycholecalciferol. It’s a biologically active form of vitamin D and is considered as one of the three calcific hormones. 1,25 dihydroxycholecalciferol has been shown to stimulate bone resorption by inducing the differentiation of osteoclasts from their precursors and increasing the activity of existing osteoclasts.It also stimulates bone mineralization and osteoblastic cell differentiation dose dependently. Osteoblasts are their target cells and act directly on the nucleus of osteoprogenitor cells. Enhances OTM when applied locally in combination with mechanical forces, i.e., help in effective bone turnover. Selin Kale et al,AJO 2004
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ORTHODONTIC TOOTH MOVEMENT Orthodontic tooth movement results from forces applied to teeth that evoke cellular responses in the teeth and surrounding structures. The force applied by orthodontic appliances alter the equilibrium of the tooth and surrounding structures resulting in tooth movement. It results from the action of many biochemical reactions happening like a cascade. www.indiandentalacademy.com
BIOCHEMICAL REACTION Orthodontic force Biophysical r{x}n
Bone deformation Viscoelastic compression of pdl
Tissue injury
Production of first messengers
hormones
prostaglandins
neurotransmitters
Production of second messengers
Camp
Cgmp
Orthodontic tooth movement
Ca++ BR
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inflammation GURKEERAT SINGH
The role of inflammation In 1815 Delabarre reported that orthodontic forces cause pain and swelling of paradental tissues along with signs of inflammation. Storey in 1973 concluded that inflammation is an integral part of the tissue response in orthodontics,a process which provides essential cells for both resorptive and depository functions that facilitate tooth movement. Davidovitch et al in 1991 proposed the following sequential and/or simultaneous events that occur during the early stages of force induced tooth movement.They are‌. www.indiandentalacademy.com
Contd‌.. Movement of PDL fluids from areas of compression into areas of tension. A gradual development of strain in all cells and ECM of the involved paradental tissues. Direct transduction of the mechanical forces to the nucleus of strained cells through the cytoskeleton leading to activation of specific genes. Release of neuropeptides {nociceptive and vasoactive} from paradental afferent nerve endings. Interaction of vasoactive neuropeptides with endothelial cells in strained paradental tissues. www.indiandentalacademy.com
Contd‌‌ Plasma extravasation from dilated blood vessels. Diapedesis or migration of leucocytes into extravascular spaces. Synthesis and release of signal molecules ie. Production of first messengers. Further leads to formation of second messengers which lead to activation of cells to participate in the remodeling of paradental tissues.
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The spread of inflammatory response is propagated and amplified by
chemical mediators www.indiandentalacademy.com
BIOCHEMICAL MEDIATORS Also called as permeability factors or endogenous mediators of increased vascular permeability.The substance acting as chemical mediators of inflammation may be released from the cells,plasma or damaged tissues itself. They are classified as mediators:1.originating from plasma 2.released by cells and a number of vascular and cellular inflammatory changes are mediated by them. These mediators are detected in increased levels in dental tissues incident to orthodontic tooth movement and secreted by existing inflammatory cells. Vandevska et al, EJO 1999
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BIOCHEMICAL TOOTH MOVEMENT Cells respond to signals from other cells and changes in the environment.Extra cellular signals can be : Endocrine signals: organs release hormones usually carried by blood to distant target cells. Paracrine signals:the cell is close to the target cell and the compound that release {local mediators} effects only the group of cells adjacent to it. Autocrine signals:respond to substances that they themselves release. Water soluble hormones bind to a receptor only at the extracellular surface of the plasma membrane thereby acting as first messengers egs: are prostaglandins,hormones, neurotransmitters. Thereby they activate enzymes that generate an increase and decrease in the concentration of intracellular signaling compounds termed second messengers{Camp,Cgmp,Ca++ and inositol}
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FIRST MESSENGERS:PROSTAGLANDINS The term prostaglandin was introduced by Von Euler.Kee Joon et al,2004 stated that they are ubiquitous mediators of local homeostasis and in particular of bone resorption in a no. of pathologic conditions including periodontitis,trauma and cancer. The precursors for prostaglandins and leukotrienes is arachidonic acid,which is released from phospholipids of cell membranes by action of phospholipase enzymes. AA are metabolized by cycloxygenase enzymes into PGs and thromboxanes and metabolism through lipoxygenase pathway yields leukotrienes . In vitro experimentation by Harell et al, suggested that PGs are major mediators of mechanical stress.Largely, on the basis of this work, Yamasaki et al,in a series of experiments with rat tooth model demonstrated that injection of PGs increased osteoclasts numbers. Further work showed that local PG injection could bring about tooth movement even in primates.This culminated in the clinical use of PGE1 to increase efficiency of orthodontic appliances. www.indiandentalacademy.com
Contd‌ Yamasaki et al,1985 concluded that orthodontic mechanical stress induced synthesis and secretion of PGs by localized cells,which stimulated osteoclastic bone resorption. IL-1 beta is an inducer of PGE and together with mechanical stress it synergistically up regulates the formation of PG in periodontal cells in vitro. Grieve et al reported that PGE levels in human GCF increased during the first 24 hours of tooth movement and returned to baseline in seven days. Kale et al,2004 reported that PGE1 and PGE2 stimulated bone resorption by directly acting on osteoclasts and proved PGE2’s stand as a well established inflammatory mediator because of its action of increasing vascularity. PGs do not fully account for bone remodeling associated with tooth movement, products of lipoxygenase system also play a role.
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LEUKOTRIENES: Metabolic products of AA through lipoxygenase pathway yield leukotrienes which were originally demonstrated in leucocytes and since they are trienes{ the back bone of the molecule has three double bonds} were called leukotrienes. Recently data shows leukotrienes are produced by bone tissue and that inhibition of leukotriene synthesis combined with mechanical stress blocks bone resorption and enhances bone formation.Therefore the modulation or mediation of orthodontic tooth movement by leukotrienes in addition to PGs is not unlikely.
Abbas et al,ajo 1989
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CELL MEMB PHOSPHOLIPIDS
Steroids inhibit
PHOSPHOLIPASE
ARACHIDONIC ACID 5-LIPOXYGENASE
5-HETE
LEUKOTRIENE B4
5-HPETE
COX1,COX2 INHIBITORS, ASIRIN INDOMETHACIN CYCLOXYGENASE INHIBIT
PROSTAGLANDIN G2
LEUKOTRIENE A4,C4,D4,E4
PROSTAGLANDIN H2 PROSTACYCLIN
PGD2 LIPOXIN A4
THROMBOXANE A2
PGE2
PGF2
LIPOXIN B4
ARACHIDONIC ACID METABOLITES www.indiandentalacademy.com
CYTOKINES: Inflammatory cells produce cytokines which mediate various stages of inflammation.Cytokines are proteins that act as signals between the cells of the immune system.They usually act locally but some act systemically with overlapping functions . Clinically important in orthodontic tooth movement are IL-1,IL6,TNF-alpha,interferons, polypeptide growth factors. IL-1 exists in two forms alpha and beta of which IL-beta is involved in bone metabolism,stimulation of bone resorption and bone cell replication Lowney et al in 1995 reported on finding increased levels of cytokines such as TNF-alpha and IL-6 in GCF of ortho treated teeth in humans.Origin of these cytokines is most likely PDL cells{Park et al,2000} Hashimi et al ,2001 showed increased levels of pro inflammatory cytokines found in tissue surrounding maxillary molars in rats after exposure to mechanical forces for 3-10 days.
Hashimi et al,ajo 2001
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NITRIC OXIDE: It’s a pleotropic mediator of inflammation,is a short lived free radical and easily diffuses across biological membrane.NO is derived from L-arginine by NO synthetase. It’s a regulator of homeostasis of bone influencing the function of osteoblasts and osteoclasts.With increase in hydraulic pressure in pdl increased production of NO due to activation of brain NO synthase by Ca++,NO then activates guanyl cyclase in PDL to increase cyclic GMP. NO shows enhanced differentiation of osteoblasts and inhibits osteoclastic activity.It also activates metalloproteinases.It plays a protective role for teeth and alveolar bone during OTM. www.indiandentalacademy.com
Contd‌. Administration of L-NAME,a general inhibitor of NO synthases to rats whose molars were removed,showed significant decrease in the rate of tooth movement.{Hayashi et al,2002} Other first messengers are neurotransmitters like Substance P,which play an important role in inflammation and pain .Also hormones like parathyroid hormone and alkaline phosphatase act as first messengers.
Nakago et al,ajo 2000
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SECOND MESSENGERS:Camp and Cgmp Cyclic nucleotide serve as mediators of the effects of extra cellular signals.Cyclic adenosine 3’-5’ monophosphate is produced by bone cells in vitro and in vivo in response to hormonal and mechanical stimuli n formed from ATP by action of enzyme adenyl cyclase. Unlike Camp which is much studied about not much is known about Cgmp,it has an intracellular regulator effect in both endocrine and non endocrine mechanisms.Like Camp its actions are believed to be mediated through phosphorylation of specific substrate proteins by Cgmp dependent protein kinases. Increase in Camp levels in mechanically stressed alveolar bone was done by Shanfeld et al.Increase in www.indiandentalacademy.com
Contd‌ Camp levels on administration of PG showed sharp and short elevations in Camp. Mechanical signal transduction involves chemical signs and the cytoskeleton second messenger molecule like Camp has been considered as primary signaling molecule ,studies suggest that cyclic nucleotides are not the primary hierarchical ladder to respond and activate cellular response.{Jones et al,1991} SHANFELD ET AL,AJO 1986
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INOSITOL PHOSPHATES Another second messenger system has also been investigated in the 1950 s by Hokin and Hokin,who demonstrated an increase in phosphate incorporation into the cell memb phospholipids. In 1980 s by Streb et al it was demonstrated that products of inositol lipid breakdown caused an increase in intracellular Ca+ +. Briefly the hydrolysis of phospotidylinositol 4,5 bi phosphonate in response to activation of surface cell receptors leads to inositol triphosphate formation, which further causes release of Ca++ from intracellular stores. Inositol triphosphate is a proven mediator of mitogenesis in a variety of cell types.its thought that in conjunction with IP3,IP4 may have role in gating Ca++ through calcium channels. The PI pathway could certainly account for many of the changes seen in mechanically deformed tissues including an elevation in Ca++ and an increase in DNA synthesis.
JONATHAN ET AL,AJO,1993
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Chemical mediators in
PAIN
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PAIN Its one of the cardinal signs of inflammation.Ortho patients frequently complain about pain sensations that begin 1-2 hr after the insertion of a new archwire or activation of the old one. Pain last from from few hours to days and patient seeks relief by consuming over the counter pain relieving drugs,such as aspirin or one of the derivatives . The mode of action of these drugs inhibit synthesis of PG and leukotrienes from their membrane bound precursor aminoacids. PGE2 is a prominent hyperalgesic and in peripheral nervous system acts as a neurotransmitter conveying signals from teeth and surrounding tissues.other pain transmitters are substance P. www.indiandentalacademy.com
Drug interactions Pharmacological agents manipulate tooth movement in both directions.two types of drugs are known to depress OTM,they are:1.Biphosphonates used in he treatment of osteoporosis eg: alendronate{fosmax}. 2.PG inhibitors eg:drugs used in treatment of artheritis –indomethacin. Acetaminophen is suggested as analgesic of choice for relieving the discomfort associated with orthodontic treatment.It’s a very weak PG inhibitor,not much anti inflammatory effects,its believed to act in the CNS and has no effect on OTM.
JOHN ET AL,AO,1996
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Osteoporosis A problem associated with post menopausal women but is associated with aging in both the sexes.estrogen therapy used in its treatment has no effect on OTM but pharmacological agents used to inhibit bone resorption pose a problem. Biphosphonates act as synthetic analogues of pyrophosphate that bind to hydroxyapatite in bone ,they act as specific inhibitors of osteoclast mediated bone resorption. Biphosphonates containing a nitrogen atom in their side chain are more potent than those without cos they can inhibit the production of isoprenoid compounds in the mevalonate pathway and hence prevent protein prenylation in osteoclasts. If orthodontic treatment s necessary in older patients its better to switch on to estrogen therapy temporarily. LIN LUI ET AL,EJO,2004 www.indiandentalacademy.com
Prostaglandin E inhibitors Are of two categories-corticosteroids,NSAIDS. Corticosteroids reduce PG synthesis by inhibition of formation of arachidonic acid. NSAIDS inhibit the conversion of arachidonic acid to PG.PGs formed by COX-1 and COX-2 inhibitors.COX-2 mediate inflammation,NSAIDS act on COX-2 and decrease rate of movement of teeth. Reports of using evening primrose oil to accelerate OTM because PGE1 is a metabolite of gamma-linoleic acid. EMEL SARI,AJO,2004
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Contd‌ Other classes of drugs that reduce tooth movment are: tricyclic antidepressants[doxepine,amitriplyline,imiprramine] anti malarial drugs[quinine,quinidine,chloroquine] anti convulsant drugs[ phenytoin] tetracycline eg:doxycycline[inhibits osteoclast recruitment] In comparative studies done it was found that ibuprofen significantly reduced PG synthesis and a marked decrease in OTM.misoprostol has insignificant inhibitory effect on local PGE2 production and the degree and rate of tooth movement increased.
Michael kehoe et al,ao,1996 www.indiandentalacademy.com
CONCLUSION Biochemical mediators have a significant role in tooth movement.Some have an accelerating effect and others have decelerating effects.A solid knowledge about the biochemical mediators in orthodontic tooth movement and their mechanism of action should provide a rationale for better and faster orthodontic treatment.However oral administrations of these mediators to facilitate orthodontic tooth movement or for stabilization requires further clinical study.
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REFERENCES
Contemporary orthodontics-Proffit. Principles of anatomy and physisology-Grabora and Tartoski. Review of medical physiology-Ganong. Textbook of orthodontics-Gurkeerat Singh. Textbook of periodontology-Glickmann. Biology of tooth movement-Davidovitch,2004. Effects of nitric oxide in orthodontic tooth movement in rats-Erol Akn et al,AJO,2004. Comparison of the effects of 1,25dihydroxycholecalciferol and prostaglandin E2 on orthodontic movement-Selin Kale et al-AJO,2004. Effects of acetaminophen,ibuprofen and misoprostol on prostaglandin E2AO,1996. Effects of exogenous prostaglandins on orthodontic tooth movement-Nanda et al,AJO,1995. Effects of PGI2 and TX2 analogs and inhibitors in orthodontic tooth movementAO,2004. Leukotrienes in orthodontic tooth movement-AJO,1989. Effects of continuous and interrupted orthodontic force on interleukin-1beta and prostaglandin E2 production in gingival crevicular fluid-Kee Joon Lee et al,AJO,2004 Evening primrose oil effects on osteoclasts during tooth movement-Sumimol et al,AO,2005. Effects of clodronate on orthodontic tooth movement and root resorption in ratsLin Lui et al,EJO,2004. www.indiandentalacademy.com
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