Saku /certified fixed orthodontic courses by Indian dental academy

BIOCHEMICAL MEDIATORS
OF ORTHODONTIC TOOTH
MOVEMENT
www.indiandentalacademy.com
INDIAN DENTAL ACADEMY
Leader in continuing dental education

INTRODUCTION
• The essence of orthodontic treatment is the
movement of teeth through bone to obtain a more
perfect dental occlusion.
• An accurate understanding and precise control over
the factors responsible for initiating and carrying out
the tissue reaction will ultimately optimize the rate of
tooth movement.
• The intelligent use of this knowledge will permit us
to modify the orthodontic appliances and treatment
regimen in order to achieve optimum tissue
response.

BONE REMODELING
• Bone is a dynamic tissue that constantly
undergoes remodeling.
• Bone remodeling is a coupled process:
Localized removal of old bone +
Replacement with newly formed bone
2/3 mineral phase
• Bone
1/3 organic matrix
Two principle bone cells – osteoblast
osteoclastwww.indiandentalacademy.com

BONE REMODELING CYCLE

BONE REMODELING
COUPLING

LOCAL REGULATION OF BONE
REMODELING
• Bone is rich source of growth factors.
• These factors are released from the bone as
it resorbs or by activated bone cells.
• They may then act in a sequential manner to
regulate all the cellular events required for
formation of bone.

• TGF-β superfamily is particularly important in the
coupling, that links bone formation to prior bone
resorption.
Bone resorption
TGF-β from bone
osteoblast precursor proliferation
BMP’S
autostimulatory effect on osteblast &
the formation of mineralized nodules

• Also , the other growth factors such as IGFs,
FGFs & PDGF effects osteoblast proliferation and
differentiation.
• These factors are all bone growth stimulants.
THE COMPLICATED INTERACTION BETWEEN
THESE FACTORS RELEASED LOCALLY IN
ACTIVE FORM AS A RESULT OF RESORPTION
PROCESS ARE RESPONSIBLE FOR
CAREFULLY CO-ORDINATED FORMATION OF
NEW BONE AT THESE SITES

BIOLOGIC PATHWAYS OF
ORTHODONTIC TOOTH MOVEMENT
• It is known that bone cells (osteoblasts &
osteoclasts) respond to orthodontic forces(OF)
by proliferation and increased activity; however
the mechanism of conversion of OF into
biologic activity is not completely understood.
• It is proposed that primary stimulus or 1st
messenger may alter cell activity through
plasma membrane.

• The plasma membrane bound enzymes
along with ca++ act to elevate cyclic
nucleotide molecules (cAMP,cGMP).
• Cyclic nucleotides have been
characterized as 2nd messenger; ie these
molecules convert membrane effects into
cellular response

Piezoelectric signals
have 2 unusual
characters:
1. Quick decay rate
2. Production of an
equivalent signal,
opposite in direction
when force is
released

BIOCHEMICAL MEDIATORS OF
ORTHODONTIC TOOTH MOVEMENTS
• Biochemistry is described as the science concerned
with chemical constituents of living cells and with
reactions and processes they undergo.
• Various biochemical substances play important role
in remodeling of tissues , during OTM.
• They can be categorized under following -
1. HORMONES
2. ENZYMES
3. PGs & LTs
4. NEUROTRANSMITTERS & CYTOKINESwww.indiandentalacademy.com

HORMONES
• Hormones are main chemical regulators of body
mechanism .
• These are usually directly released into the blood
stream from specific glands .
• These elicit different reactions in different tissues
with only certain tissues responding to a given
hormone.
• As specific tissue cells may respond selectively to
a hormone , these are called as Target cells.

• Hormones may directly enter the cells and
regulate the mechanism or bind to the cell
membrane and elicit a 2nd messenger
response from cytoplasm.
• cAMP is designated as a second messenger.
1st messenger
GLAND TARGET CELL
hormone
2nd messenger
TARGET CELL METABOLIC EFFECTS
cAMP

PARATHROMONE
• PTH causes a rise in blood calcium level
by following mechanism –
1. It causes bone resorption.
2. It converts vit D into its active form 1,25-
dihydroxycholecalciferol.
3. It causes reabsorption of calcium from
the distal segment of nephron.
• PTH acts by stimulating adenyl cyclase
and cAMP production

Action may be divided into –
• INSTANTANIOUS REGULATION of calcium is
accomplished in seconds by selective transfer of
calcium ions into and out of bone fluid.

• Bone fluid is seperated from extracellular fluid by
osteoblasts or relatively thin bone lining cells.
• A decrease in the serum calcium level stimulates
secretion of PTH, which enhances transport of
ca+2 from bone fluid into osteocytes and bone-
lining cells.
• The active metabolite of vit D(1,25 D) enhances
the pumping of calcium ions from bone-lining
cells into extracellular fluid.
• Thus Ca+2 is transported across bone-lining
cells, resulting in a net flux of calcium ions from
bone fluid to extracellular fluid.

• SHORT TERM CONTROL of calcium levels
affects rates of bone resorption and formation
within minutes.
• PTH acting in concert with 1,25 D accomplishes
these important tasks-
1. Enhances osteoclast recruitment from
promonocyte precursors.
2.Increase the resorption rate of existing
osteoclasts.
3.It may supress the rate at which osteoblast form
bone.

• LONG TERM REGULATION of metabolism
has profound effects on skeleton.
• Mass and geometric distribution of bone are
strongly influenced by load history
(biomechanics) and sex hormone status.
• PTH is primary mediator of frequency of
remodeling.
• PTH mediated activation frequency
determines mean bone age.

• Surprisingly , however PTH receptors
are not found on cell membranes of
osteoclast but are found on osteoblast
and osteocytes.
• This indicates that control of
osteoclasts is via paracrine agents
secreted by other cells, probably by
preosteoblast and mesenchymal cells.

• Midgett et al (1981) studied the effect of altered
bone metabolism on OTM.
• Experimental dogs fed with a low calcium diet
showed elevated endogenous PTH levels(state
of hyper parathyroidism).
• The resulting high turnover osteopenia
contributed to enhanced rate of OTM because of
lower bone density and elevated remodeling
rate.
• (unfortunately this approach is not applicable for
clinical use because of considerable amount of
systemic bone loss )

VITAMIN D
• Cholecalciferol is synthesised in skin irradiated by UV
light, hydroxylated in liver at #25 position and then
hydroxylated in kidney at #1 position to produce the
active metabolite 1,25 dihydroxycholecalciferol.
• Biochemical effects of vit D –
a) intestinal villi – promotes absorption of ca++.
b) bone – mineralisation of bone is by increasing the
activity of bone osteoblast .
- it coordinates the remodeling action of osteoblast
and osteoclast.
c) Renal tubules- reabsorption of ca++ and
phosphorous.

• Monte k collins and Peter M sinclair (1988)
studied the local use of vit D to increase the rate of
OTM.
• They concluded that –
1) a weekly intraligamentous injection of 1,25 D soln.
produced significantly increased amount of OTM
after 21 days of experimental period.
2) there was increased rate of recruitment and
activation of mononuclear osteoclast resulting in
greater bone resorption.
3) no obvious clinical, microscopic and biochemical
side effects were noted.

• Local injection of 1,25 D significantly increased
the rate of OTM.
• Although similar findings have been reported with the
use of pulsed electromagnetic fields, direct currents
and PGs, but these techniques represent completely
different mechanism of action from 1,25 D.
• Pulsed fields and direct electric currents activate
osteoclasts by increasing the levels of cAMP and
cGMP which acts as 2nd messenger at the level of cell
membrane.
PGs have been shown to act in the similar fashion.

However 1,25 D acts directly on nucleus of
circulating monocytes and progenitor cells.
This allows a cellular activation that is totally
independent of cyclic nucleotide cascade.

• Microscopically, the experimental teeth displayed
faster than normal recruitment of resorptive cells.
• Among the local changes that are known to
contribute to the fusion of mononuclear osteocyte
cells are an increase in the ca++ concentration and
decrease in pH, both of which occur only after bone
resorption has preceded for a while.
• Therefore , the rate limiting step in OTM may be the
time required for adequate recruitment of osteoclast
precursor cells.
• In this regard 1,25 D seemed to be efficatious in
increasing the rate of alveolar resorption.

SEX HORMONES
• Sex hormones have profound effect on bone.
• Androgens build and maintains
musculoskeletal mass.
• The primary hypertrophic effect of androgen
is to increase the muscle mass.
• The anabolic effect on bone is a secondary
biomechanical response to increase loads
generated by the enhanced muscle mass.

• ESTROGEN, on the other hand has direct effect on
bone; it conserves skeletal calcium by suppressing
the activation frequency of bone remodeling.
• At menopause, enhanced remodeling activation
increases turnover.
• Because a slight negative calcium balance
associated with each remodeling event, a
substantial increase in the turnover rate can result in
a rapid bone loss, leading to symptomatic
osteoporosis.
• Thus, orthodontist should avoid a treatment plan
that is overly dependent on orthodontically induced
anabolic remodeling in post menopausal females.

ENZYMES
• Enzymes in blood serum are either normal or
abnormal constituents.
• Enzymes not normally found in serum are
derived from tissue damage.
• The abnormal serum enzymes ie non-
plasma specific enzymes are of 2 types-
1. secretory – function in digestion
2.intracellular – perform role in metabolism

• Different type of intracellular enzymes are
alkaline phosphatase, acid phosphatase,
creatinine kinase, serum transaminase,
lactate dehydrogenase etc.
• Out of these alkaline phosphatase , AP and
LDH are the ones which plays important role
in metabolism and tissue degradation
incident to OTM.

• Phosphatase changes have been described in
orthodontically treated tissues.
• Few investigators have reported increased AP and
decreased Alkaline Phosphatase activity on the
pressure side & increased Acid and Alkaline
Phosphatase activities on the tension side of
orthodontically treated tooth upto 7 days after
appliance activation in rats. As no description past 7
days was made, it is likely that reversal in activity of
these enzymes was missed in these studies.

• A study was done by Keeling and King (1993) to
examine time course of phosphatase changes
during an entire tooth movement cycle in both the
serum and alveolar bone.
• During OTM in rodent model-
- early wave of resorption (3 to 5 days)
- reversal (5 to 7 days)
- late wave of formation (7 to 14 days)
• Resorbing cells (osteoclasts and macrophages)
- high AP & TRAP activities.
• Bone forming cells (osteoblasts)
- high Alkaline Phosphatase activities.www.indiandentalacademy.com

• AP, TRAP and Alkaline Phosphatase changes in
serum and alveolar bone clearly demonstrated that
bone turnover is not balanced in short term during
OTM.
• Instead there seems to be an early preponderance
of bone resorption followed by later period when
bone formation is primary.
• This finding confirms earlier reports of bone turnover
characterized by tandem periods of activation,
resorption , reversal and formation, occurring after
orthodontic force application.

• The early peak in serum AP & TRAP preceded the
peak in bone.
• This early serum peak occurred during the induction
(activation) phase of bone turnover cycle during which no
bone changes could be quantified.
• The serum peak fell of early (day 3) and remained
depressed until the end of observation period.
• The peak in bone AP & TRAP activities lasted longer (from
day 3 to 7) and reversed between days 7 & 10, remaining
depressed at 10 & 14 days.
• The finding that the serum peak in these enzyme activities
preceded their appearance in bone suggests that
osteoclasts and preosteoclasts may be detectable during
their migration to the treated PDL.

• There was a peak in Alkaline Phosphatase activity
in both serum & alveolar bone at day 7, reflecting
formation that occurred between 7 and 10 days.
• In addition, a second , but significant , late peak at
day 14 was observed in serum but not in bone.
• The timing of serum Alkaline Phosphatase
changes in bone , confIrms previous observations
that osteoblasts are present locally without a
requirement for significant blood borne migration.

Histochemistry of enzymes associated with tissue
degradation incident to OTM
(Lilja et al )
• Study was done on the activity of AP
& LDH in PDM and alveolar bone as indicators of
bone resorption and tissue damage during OTM.
• Non treated rats – cells with high AP activity were
randomly distributed along the bone surface.
• Low orthodontic force – rapid redistribution of cells
with high AP activity to the pressure zones.
• Low forces caused no change in distribution and
activity of LDH

• High forces - changes in enzyme activity similar
to those induced by low forces.
• However there was one definite difference - a
zone lacking both AP & LDH developed in
compressed parts of PDM.

• It was concluded,
1) high activities of AP & LDH in PDM reflects a high
metabolic activity and a rapid turnover of connective
tissue.
2)AP is a lysosomal enzymes which has a high activity and
bone resorbing cells.
During 1st 10 hrs of orthodontic treatment the distribution
of AP containing cells change from a non specific
distribution to local accumulation in the pressure zone.
The mechanism which direct osteoclastic resorbtive
activity to specific site on bone surface is not known.
Piezoelectricity, streaming potential and chemotaxis due
to local tissue damage have been proposed.

3)Compression of PDM to a certain degree induces
hyalinization of most compressed areas.
Neither LDH nor AP activity was demonstrated in
these areas.
The hyaline zone is area of aseptic necrosis . This
hyaine zone is resistant to degradation and persist
for long time in the pressure zone, depending on
the magnitude of force.
The lack of lysosomal enzymes in hyaline zone
explains why the elimination of the hyaline zone is
a slow process .

PROSTAGLANDINS AND
LEUKOTRIENES
• PGs and LTs are modulators of adenyl
cyclase.
• Effects restricted to cell of origin and
neighbouring cells.
• Action depends on modulating cAMP
levels and intracellular flow of Ca+2

PROSTAGLANDINS
Parent compound – Prostanoic acid.

PGs are not stored in tissues,rather they are
produced from membrane phospholipid stores.

Mechanical distortion of cell
PGE2 from membrane phospholipids
Subseqent binding of extra-cellular PGE2
to cell surface receptors
Activation of adenyl cyclase & cAMP pathway

• PGs secretion regulated by FEED-BACK
mechanism.
• PGs promote bone resorption by:
- number & size of osteoclasts.
- Activation of existing osteoclasts.
- Induction of collagenase production
by mechanically deformed cells.
• PGs of E & F series are powerful mediators of
bone resorption

LEUKOTRIENES
• LTs are compounds closely related to
PGs,that are produced by conversion of
arachadonic acid via lipo-oxygenase
pathway.
• There is interaction b/t cyclo-oxygenase
& lipo-oxygenase pathway.
• Inhibition of one pathway of arachadonic
acid will shunt the effect into increase in
the conversion via the other pathway.

• BUT inspite of PGs levels ,a
selective inhibition of LTs synthesis
cause significant reduction in tooth
movement.

There are several mechanisms through
which LTs might affect tooth movement:
1. Mediator of inflammatory response.
2. Collagenase systhesis.
3. Facilitate Ca+2 movement during chemotactic
activity of neutrophils.

NEUROTRANSMITTERS
• Physical distortion imposed by Orthodontic
forces on paradental tissues,has effects on
peripheral nerve fibres and terminals.
• Neuropeptides stored in nerve terminals
within the PDL either may be released into
the extracellular space or streamed towards
the ganglion.

Neuropeptides, particularly SP, VIP &
cGRP have been shown to affect bone
cells directly or through their effects on
vascular system.

SUBSTANCE P (SP)
• First peptide to be proposed as neurotrasmitter.
• Synthesised ribosomally in the cell bodies of small
diameter primary afferent neuron, then transported
by axoplasmic flow to terminals centrally or
peripherally.
• There it is stored & released on neuronal
stimulation.
• Peripherally released SP interacts with blood
vessel cells, causing vasodilation, which results in
extravassation of plasma & migration of leukocytes
into extravascular tissues.

• SP has been identified in dental tissues (in
fibres around blood vessels in dental pulp &
PDL)
• Role of SP in bone remodeling was studied
in arthritic joints.
Severe arthritis more SP containing
primary afferent
less severe arthritis less SP containing
primary afferent

• When SP incubated for 48 hrs with cultured
human stnoviocytes from arthritic patient :
- PGE2 & collagenase release
- cell proliferation
VASOACTIVE INTESTINAL POLYPEPTIDE
(VIP)
• First isolated from hog intestinal tissue.
• Contains 28 amino acid.
• Potent vasodilator – hypotensive effects on
most vascular bed.
• Shown to stimulate bone resorption in-vitro, in a
dose related manner , through c-AMP mechanism.

Orthodontic force
Movt. Of tissue fluid in and out of pdl
Distortion of nerve endings
Release of stored neurotransmitter
Pressure sensation,pain Interaction with endothelial cells
vasodilation
Extrusion of plasma,PGs & leucocytes
Synthesis and secretion of cytokines
Interaction with pdl fibroblasts
& alveolar bone cells
Incresed level of intracellular
2nd messengers(Ca++,cAMP,cGMP)
Synthesis & secretion of
Cell products,cell proliferation,
Motility etc.
ROLE OF NEUROTRANSMITTERS IN OTM

CYTOKINES
• Cytokines are small proteins produced by
cells which modify the behavior of other cells.
• Inflammatory cell produces numerous
cytokines.
• Some cytokines particularly IL-1α,IL-1β,TNF-
α and γ-INF have been implicated in
mediation of bone remodeling process.

• Source of IL-1:Mononuclear phagocytes
keratinocytes
fibroblasts
endothelial cells
2 distinct gene products cloned in
humans: IL-1α and IL-1β

How do CYTOKINES induce
mechanically induced bone
remodeling?

Although effective cell of bone resorption is
osteoclast,studies demonstrate that
osteoblast and not osteoclast exhibit
receptors for PTH, Vit-D metabolites and
PGs, indicating that osteoclast recruitment
and activity involves cells of osteoblast
lineage.

How osteoblasts transmits
signals??

ROOT RESORPTION
• OTM is possible because of greater
resistance of cementum than bone to
resorption.
• However, its proved that most teeth
moved orthodontically undergo some
minor degree of root resorption followed
by repair.
• The initial breakthrough of cementum is
connected with removal of hyalinized
parts of PDL.

• Macrophages in various stages of
maturation accumulates around the
hyalinized zone & remove necrotic tissue.
• The barrier effect of the cementoid tissue
behind the hyalinized zone seems to be
reduced or gone, and macrophages fuse &
become resorbing cells (clasts) .
• A small breakthrough is adequate to start
the process.

• When a resorption lacuna has been formed , the
ensuing events will depend on whether application
of force is continued.
• If it is, resorption will continue.
• If application of force is absent or below certain
level, repair will commence in resorption lacunae
with the deposition of cementum.
• Thus, rest periods without force application
should be included in treatment of patients with
a tendency for root resorption.

PHARMACOLOGICAL CONTROL
OF TOOTH MOVEMENT
2 Types of drugs are known to depress
the response to orthodontic force -
1. Bis-phosphonates
eg: alendronate(fosamax)
2. Prostaglandin inhibitors
eg: indomethacin

Drugs that affect PG activity falls in 2
categories:
1. Corticosteriods & NSAIDs.
2. Agents that have mixed agonistic and
antagonitic effects on various PGs.

Any drugs that accelerate tooth
movement??
• Relaxin
• Substances with angiogenic activity
-estrogen
-NO
-Naltrexone
• Collagenase

conclusion
The next major change in the way orthodontics will
be practised in future, is in clinicians ability to
change the host to respond to –
mechanical forces applied to the teeth
or propensity for teeth in new position to relapse.
The means of doing so is through expanding the
understanding of BASIC BIOLOGY OF TOOTH
MOVEMENT

REFERENCES
1. The biology of tooth movement
-Norton and Burstone
2. Orthodontics -current principles and
technique
-Graber and Vanarsdal
3.Contemporary Orthodontics
-William R.Proffit

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