Chemical mediators influencing orthodontic tooth movement

CHEMICAL MEDIATORS
INFLUENCING
ORHODONTIC TOOTH
MOVEMENT
www.indiandentalacademy.com

OVER VIEW
•Tooth structure (pdl)
•Sensors in tooth structure.
•Physiologic tooth movement
•Orthodontic tooth movement

•Precondition for tooth movement
•Factors influencing
•In which tooth movement these mediators
are found
•Drug interaction with chemical mediators

Tooth structure:
• each tooth is attached to and seperated
from the adjacent alveolar bone by a
heavy collagenous supporting structure.
• Width – approximately 0.5mm around all
parts of roots

• The major component of the ligament is
a network of parallel collagenous fibers
inserting into cementum of the root on
one side and dense bony plate , lamina
dura on other side.

• These supporting fibers run at an
angle attaching farther apically on
the tooth than on the adjacent
alveolar bone.
• This arrangement resists the
displacement of the tooth expected
during normal function.

The other major constituents of the
periodontal ligament are
• The cellular elements, including
mesenchymal cells of various types along
with vascular and neural elements
• The tissue fluids.

• Both play an important role in normal
function and in making orthodontic tooth
movement possible.
• Principle changes in periodontal ligament are
– undifferentiated mesenchymal cells & their
progeny in the form of fibroblasts and
osteoblasts

• Undifferentiated mesenchymal cells under tension
differentiate into osteoclasts & cementoclasts, these
same cells under pressure differentiate into
osteoblasts, fibroblasts and cementoblasts.
• Periodontal ligament is not highly vascular, but it
does contain blood vessels and cells from the
vascular system.

• Nerve endings are also found with in the
ligament, both the unmyelinated free endings
associated with perception of pain & the more
complex receptors associated with pressure &
positional information(proprioception)
• Nerve bundles pass into the periodontal
ligament from the periapical area & through
channels from the alveolar bone that follow
the course of the blood vessels
karanza

• They divide into single myelinated fibers,
which ultimately lose their myelin sheaths &
end in one of four types of neural termination.
• Free endings which have a tree like
configuration & carry pain sensation.
• Ruffini – like mechanoreceptors , located
primarily in the apical area.

• Coiled Meissner’s corpuscles , also
mechanoreceptors, found mainly in the
mid root region.
• Spindle like pressure & vibration
endings which are surrounded by a
fibrous capsule & located mainly in the
apex

• PDL space is fluid filled. This fluid is
derived from the vascular system.
• A fluid filled chamber with retentive but
porous walls could be a description of shock
absorber & in normal function , the fluid
allows the PDL space to play this role.

Physiologic tooth movement:
• if an object is subjected to set of forces but
remains in the same position, those forces
must be in balance or in equilibrium.
• Teeth normally experience forces from
masticatory effort, swallowing & speaking
but do not move.

• If a tooth is subjected to a continuous
force from the orthodontic appliance, it
does move.
• The force applied by the orthodontist
has altered the previous equilibrium ,
resulting in tooth movement.

• One of the factors which contribute to
the dental equilibrium is the periodontal
fiber system.
• If a tooth is lost, the space tends to close,
in part because of the forces created by
the transseptal fibers in the gingiva.
• This was demonstrated experimentally
on monkeys. www.indiandentalacademy.com

• PL also influences eruption of teeth.
Eruption mechanism remains
potentially active through out life.
• Since a tooth can begin to erupt again
many years after eruptive movements
are apparently ceased, if its antagonist
is extracted.

Orthodontic tooth movement
• Orthodontic tooth movement is induced by
mechanical stimuli and facilitated
by remodeling of the periodontal ligament &
alveolar bone.

Bone
• Bone is of 2 types
1. Cortical
2. & Cancellous .

Cortical bone
• Cortical bone looks dense & compact & constitutes 80% of
the skeleton forming the inner &outer layers of tubular
appearing appendicular bone,inner & outer tables of flat
bones & inner & outer surfaces of vertebral bodies.
• Cortical bone is engineered to protect vital organs.it
consists of haversian systems with 4 – 20 circumferential
rings of concentrically arranged lamellae that encompasses
a central canal.
• Haversian systems in cortical bone function as buttresses.

Cancellous bone
• Interposed between cortical bone is the spongy
looking cancellous bone.
• A 3 dimensional lattice of trabeculae is the hall
mark of this struicture.
• Spatial orientation of trabeculae is random.
• Rather than being engineered for loading
cancellous bone has been designed to respond
rapidly to physiologic requirements.

• Bone consists of 4 microstructural components
1. Cells –
2. Organic matrix
3. Inorganic matrix
4. Soluble signalling factors
•Osteoblasts
•Osteocytes
•osteoclasts

osteocyte
osteoclast
osteoblast

• All cells are derived from mesenchymal cell
lineage.
• Undifferentiated mesenchymal stem cells
For bone formation
during embryogenesis
Determined
osteoprogenitor
cells
Inducible
osteoprogenitor cells
For fracture repairwww.indiandentalacademy.com

• According to Brighton following fracture with in 12
hrs polymorphic mesenchymal cells appear
providing preosteoblastic cell resource.
• Depending on the presence of environmental cues
such as nutrient supply, specific growth factors,
blood vessels & mechanical stability , they can
convert either to cartilage forming chondrocytes or
bone forming osteoblasts.

Osteoblasts
• Osteoblasts are metabolically active secretory
cells that express soluble signaling factors ex:
BMP’s, TGF- beta, insulin like growth factor I &
II , interleukin – 1 & platelet derived growth
factor & osteoid.
• Expression of these factors by osteoblasts occurs
during bone embryogenesis, maintenance(ex:
remodeling) & repair.

• During remodeling , osteoid is produced at the
rate of 2 - 3 micrometers per day at a thickness of
20 micrometers.
• After a maturational period of 10 days, osteoid
mineralises at a rate of 1- 2 micro meters per day.

Osteocytes
• These are relatively inactive cells. Their subdued
metabolic activity is crucial to bone viability & to sustain
homeostasis.
• The complex processes of homeostasis are regulated by
physiologic interactions among cells, tissues, organs &
signaling factors such as harmones & growth factors that
meticulously titrate intra & extra cellular levels of
cationic & anionic moieties

• Vitality of bone is maintained through a network of
osteocytic cytoplasmic processes that traverse
canaliculi.
• This highway system enables osteocytes to interact
through gap junctions & permits signal transmission
to osteoblasts from osteocytes & from osteocytes to
osteoblasts.

• Osteocytes,osteoblasts & osteoclasts are the
cellular crafts men performing the managerial
roles of calcium regulation & bone
homeostasis, physiological processes
fundamental to modeling & remodeling.

Osteoclasts
• Granulocytic – precursors found in bone marrow
enter the circulation as monocytes , and through
asynchronous fusion, produce a multinucleated
cell with an average of 10 – 12 nuclei known as
osteoclast.
• Osteoclasts have a ruffled border, possess
calcitonin receptors, produce tartarate resistant
acid phosphatase.

• Interleukin 1,3,6& 11 and probably TNF – alpha
along with transforming growth factor – alpha
appear to be important modulators for
development of osteoclasts.
• Evidence appears to implicate a dynamic interplay
between soluble factors, osteoblasts & osteoclasts.

1 – 25 – dehydroxy vitamin – D3
binds with osteoblasts
Expression of osteoclast
differentiation factor
Osteoclast progenitors that have been
primed by exposure to soluble factors such
as interleukins.www.indiandentalacademy.com

• When osteoblast disperse from bony surfaces, in
response to PTH, an exposed osteoid –
mineralised run away provides osteoclasts with an
oppurtunity to attach.
• Attachment involves surface adhesion molecules
(integrins) & proteins.
• Osteopontin , a sialophosphoprotein, secures
osteoclast docking to bone through an arginine –
glycine aspartic acid motif.

• The attachment perimeter is referred to as the
zone of attachment & with in this zone, a
ruffled border develops.
• The ruffled border constitutes the resorptive
teritory of the osteoclast where enzymatic
breakdown of the bone surface occurs.

• The zone of attachment between the ruffled border
& the bone isolates the surface microenvironment ,
enabling aditional enzymes such as carbonic
anhydrase to decrease ph thus promoting
solubilization of the inorganic matrix of Ca & P &
exposing the organic matrix to these proteolytic
enzymes.

• Osteoblasts are prompted to express modulators of
osteoclastic activity following osteoblast receptor
binding to either PTH or 1-25 dihydroxy vitamin –
D3 .
• This has been verified by invitro experiments
revealing that these harmones have no effect on bone
reorption when added to cultures containing only
osteoclasts, however osteoclastic activity develops
when osteoblasts are added.www.indiandentalacademy.com

Matrices
organic
inorganic
35 % of dry wt.
Type I collagen.
10 % non collagenous
proteins.ex:BMP
Non collagenous
proteins are PG or GAG
Modulate cellular
attachment.
60 – 70 % of dry wt.
99% Ca, 85 % P, 40 – 60
% Na & Mg

• During skeletal embryogenesis ,
homeostasis & repair , osteoblasts
vectorially express an organic based
product, osteoid, that is primarily composed
of type – I collagen & is the template for Ca
& P deposition.

Soluble factors
• In 1938 Levander stated that bone regeneration
takes place as a result of some specific bone
formation substance activating the non specific
mesenchymal tissue.Later on the term
osteoinduction is used to describe the same
phenomenon.
• These soluble factors especially bone morphogenic
proteins are necessary for osteoinduction.

• BMP’s are a group of morphogenic proteins
that direct embryologic development of
cells, tissues & organs in adition to
performing crucial roles in post fetal
physiology.

• Precondition for this remodeling activity is
inflammatory response.
• Inflammation is local response of host to tissue
injury by microbial material, chemical or physical
stimulus.
Precondition for orthodontic
tooth movement

• Inflammation is characterized by redness,
heat,swelling,pain & loss of function.
• These visual changes are the result of
1. Vasodilatation with increased vessel permeability
& blood flow.
2. Exudation of fluids.
3. Leukocyte migration into extra vascular spaces

•The spread of inflammatory
response is propagated as
well as amplified by

Chemical mediators
• Also called permeability factors or endogenous
mediators of increased vascular permeability.
• The substances acting as chemical mediators of
inflammation may be released from the cells,
plasma or damaged tissue itself.
• They are classified as
1. Mediators released by cells
2. Mediators originating from plasma.www.indiandentalacademy.com

Source mediator main action
Mast cells, histamine increase permeability
Basophils,
Platelets
Platelets seratonin increase permeability
& tissue damage
Inflamatory lysosomal enzymes inc permeability
Cells prostaglandin vasodilatation
leukotrienes, cytokines fever,tissue damage.
oxygen metaboliteswww.indiandentalacademy.com

Inflammatory mediators &
orthodontic tooth movement
• Vascular & cellular inflammatory changes are
mediated and ,maintained by a number of
biochemical substances.
• These mediators are detected in increased levels
in dental tissues incident to orthodontic tooth
movement and are secreted by existing
inflammatory cells.
Vandevska
et al
EJO
1999

• Interleukin – 1 and tumor necrosis factor are
pro inflammatory cytokines known to induce
synthesis of various proteins which in turn
elicit acute & chronic inflammation.
• A marked increase in intensity for interleukin
– 1 & TNF is noticed in the cells of PDL & alv
bone of orthodontically moved cat canines,
implying their activity in bone remodeling
processes.

• Cells of nervous, immune, & endocrine systems
become involved in the activation & response of
the periodontal ligament & alveolar bone cells
during tooth movement.
• Orthodontic forces induce increased levels of
prostaglandins & leukotrienes in both periodontal
& bone cells.
• According to Mostafa etal movement is mediated
through local action of prostaglandins.www.indiandentalacademy.com

• Arachidonic acid present in the membrane phospholipid
of cells , can be released by phospholipidases activated
by cellular damage or by any non destructive pertubation
of the membrane.
• Arachidonic acid is metabolized by two main enzyme
path ways: cyclo-oxygenase, & lipo- oxygenase.
• The products of arachidonic acid metabolism, namely
PG’s of E & F series , prostacyclines & the leukotrienes
are the integral components of the inflammatory reaction.
M
ichaelj.kehoe
AO
96

• Inflammatory cells produce cytokines which
mediate various stages of inflammation.
• Cytokines are proteins that act as signals
between the cells of immune
system.
• They usually act locally but some act
Alhashimi etal
AJO 2001

• The various cytokines are interleukin – 1,
interleukin – 6 & tumor necrosis factor – alpha.
• IL-1 exists in 2 forms, alpha & beta, of which IL-1
beta is the one mainly involved in bone
metabolism,stimulation of bone resorption, &
inhibition of bone formation.
• IL-1beta may act synergistically with TNF- alpha
and is a powerful inducer of IL-6.

• Il-1beta,IL-6 and TNF-alpha were suggested to stimulate
bone resorption & bone cell replication.
• Several positive and negative transcription factors function
in a concerted manner to regulate the transcription of
cytokines at the promoter or intron region.
• It is also common for the transcription of cytokine genes to
initiate immediately on activation & to shut down quickly

Drug interaction
• Pharmacological agents manipulate tooth movement in
both directions.
• Factors that enhance tooth movement are vitamin –D &
direct injection of prostaglandin into periodontal
ligament.
• Drugs that inhibit tooth movement are frequently
encountered.

• Two types of drugs are known to depress
orthodontic tooth movement. They are
1. Bisphosphonates used in the treatment of
osteoporosis. Ex : alendronate (fosmax.)
2. Prostaglandin inhibitors. Ex : drugs used in the
treatment of arthritis like indomethacin.

Osteoporosis
• It is a problem particularly encountered in post
menopausal females but is associated with aging in both
sexes.
• Estrogen therapy , which is used frequently to prevent
loss of bone in older women , has no impact on
orthodontic treatment.
• But pharmacological agents that inhibit bone resorption
present a serious problem.

•Bisphosphonates are synthetic analogues of
pyrophosphates that bind to hydroxyapatite in bone .
•They act as specific inhibitors of osteoclast mediated
bone resorption.
•If orthodontic treatment is necessary in older patients it
is better to switch over to estrogen at least temporarily.

Prostaglandin E inhibitors:
•Prostaglandin E inhibitors are of two categories.
They are
•Corticosteroids & NSAIDs.
•Other agents that have mixed agonist &
antagonist effects on various prostaglandins.

•Prostaglandins are formed from arachidonic acid
which in turn is derived from phospholipids.
•Corticosteroids reduce prostaglandin synthesis by
inhibiting the formation of arachidonic acid.
•NSAIDsinhibit conversion of archidonic acid to
prostaglandins.

• Other classes of drugs which reduce tooth movement are
• Tricyclic antidepressants (doxepin,amitriptyline,
imipramine.)
• Anti arrhythmatic agents( procaine)
• Anti malarial drugs ( quinine, quinidine, chloroquine.)
• Anticonvulsant drug Phenytoin.
• Tetracyclines ex: doxycycline (inhibit osteoclast
recruitment)

John etal AO 96
• Acetaminophen is suggested as analgesic of choice for
relieving the discomfort associated with orthotreatment.
• It is a very weak PG inhibitor.
• Possess no significant anti- inflamatory effects.
• Exact mechanism by which it relieves fever & pain is not
known, it is believed to act in the CNS.
• It has no effect on orthodontic tooth movement.

Michael kehoe
etal AO 96
• Study was done to compare the effect of
Acetaminophen, ibuprofen, & misoprostol.
• It was found ibuprofen significantly decreases PG
synthesis in pdl of guinea pigs.there is a marked
decrease in degree & rate of tooth movement.
• Acetaminophen decreases peripheral PG production.
But there is no significant effect on tooth
movement. www.indiandentalacademy.com

•Misoprostol has insignificant inhibitory effect on
local PGe2 production.the degree & rate of tooth
movement increased. This acceleration is attributed
to the enhanced bone resorbing activity of PGe1.

Conclusion:
•Biochemical mediators have a significant role in
tooth movement. Some have an accelerating effect
& others have decelerating effects. However oral
administration of these mediators to facilitate
orthodontic treatment by enhancing tooth
movement or for stabilisation requires further
clinical study.

Chemical mediators influencing orthodontic tooth movement

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Chemical mediators influencing orthodontic tooth movement