Biochemical Mediators Ortho / Orthodontic Courses by Indian Dental Academy

INDIAN DENTAL
ACADEMY
Leader in continuing dental education
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Bio chemical mediators
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
patients 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 .
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 information-
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.
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.
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 25
osteoblast
osteoclast
osteocyte
.
1,25 Dihydroxycholecalciferol.
Its 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
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.
BIOCHEMICAL REACTION
Orthodontic force
Biophysical r{x}n
Tissue injury
Viscoelastic compression of pdl Bone deformation
Production of first messengers
prostaglandins neurotransmitters hormones
Production of second messengers
Cgmp Ca++ Camp
inflammation
BR
Orthodontic tooth movement
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.
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.
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.
The spread of inflammatory
response is propagated and
amplified by
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
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}

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.

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 PGE2s
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.
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 www.indiandentalacademy.com

CELL MEMB PHOSPHOLIPIDS
ARACHIDONIC ACID
5-HPETE
PROSTAGLANDIN G2
PROSTAGLANDIN H2
PROSTACYCLIN THROMBOXANE A2
PGD2 PGE2 PGF2
5-HETE
LEUKOTRIENE A4,C4,D4,E4
LIPOXIN A4 LIPOXIN B4
PHOSPHOLIPASE
5-LIPOXYGENASE
CYCLOXYGENASE
LEUKOTRIENE
B4
Steroids inhibit
COX1,COX2 INHIBITORS,
ASIRIN INDOMETHACIN
INHIBIT
ARACHIDONIC ACID METABOLITES
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,IL-
6,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 www.indiandentalacademy.com
NITRIC OXIDE:
Its 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.
Its 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.
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 www.indiandentalacademy.com
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
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 www.indiandentalacademy.com
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
Chemical mediators in
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.
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.Its 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 www.indiandentalacademy.com
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
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 www.indiandentalacademy.com
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.
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 E2-
AO,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 movement-
AO,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
rats- Lin Lui et al,EJO,2004.

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