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Abstract Biology of Orthodontic tooth movement has always been an interesting field to Orthodontist.
At present many advanced researches are being undertaken globally at different genetic and
cellular levels in this arena. Starting from external stimulus such an orthodontic force to the
mechanical expression of the same in periodontal ligament and bone this review article
unfolds cascade of events occurring at cellular level yielding to gene expression ultimately
affecting the bone resorption or bone apposition. This whole cascades passes through various
chemical, electrophysical mediators of tooth movement. This article also discusses various
clinical applications of knowledge of histological aspects of orthodontic tooth movement.
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J Ind Orthod Soc 2006; 39:155-164
2. The second type of cells, which are of interest are Osteoprogenitor cells are mesenchY!11al, fibroblast
the osteocytes. They were histologically thought to like cells, regarded to form a stem ,cell population
be trapped osteoblasts in the matrix and whose to generate osteoblasts. They are situated in the
function was considered to provide support and vicinity of blood vessels of POL. Bone lining cells
sustenance to the bone. Osteocytes are now are the undifferentiated flattened cells lining the
understood to be very proprioceptive and responsive bone surface. They may represent active
cells of bone 3 • It has been demonstrated by Skerry et osteoblasts, but further confirmation is needed.
ai, that an intermittent force within physiologic
limits has an effect in increasing the expressions of In essence, bone remodeling is orchestrated by cells
glucose-6-phosphate dehydrogenase, 3H-urinidine, of osteoblast linage and involves a complex network
c-fos, and insuline - like growth factors-I in the of cell to cell and cell to matrix interactions
osteocytes within six hours after intermittent loading involving systemic hormones, locally produced
cytokines, growth factors, many of which are
at physiological strain magnitude 4 •
sequestrated within the bone matrix, as well as the
3. The third type of cells viz. osteoclasts which mechanical environment of cells
differentiate from monocyte-haemopoietic cells.
Active osteoclasts exhibit high content of a specific Cascade of events that follow after
chemical marker, tartrate resistant acid phosphatase application of orthodontic force
(TRAP), which participates in signaling active bone
Histologically, a typical Orthodontic tooth movement
resorption.
(OTM) as described earlier by 'Schwartz' presents with
Many chemical mediators of macrophage fami Iy are alveolar bone modeling, i.e. apposition of bone on its
known to influence osteoclast differentiation. They surface to alter shape and size on the tension side. A
are cytokines (e.g.: tumor necrosis factor TNF, simultaneous process is the activation of osteoclast
interleukin-1 alpha, 6-alpha), certain growth factors precursors and then osteoclastic bone resorption, which
(e.g .: macrophage colony stimulating factor, is followed by bone formation to repair the defect
granulocyte, macrophage colony stimulating factor) predominately on the pressure side.
and Prostaglandins. Evidence suggests that osteoblast
Schwartz's concept was once again proved right as we
itself regulates the differentiation of osteoclasts. 2 The
analyse the study carried out with the aid of modern
"talk" between an osteoblast and osteoclast is
technologies available today like the three-dimensional
accomplished through an osteoblast membrane bond
evaluation of periodontal remodelling during
RANK ligand (receptor activator nuclear factor kB
orthodontic treatment done by Robert A.W. Fuhrmann 7 •
ligand), which can interact with developing
In this study on 21 adult patients, 2 or 3 high resolution
monocytes to cause them to differentiate eventually
computed tomography (HR-CT) examinations were
into osteoclasts. An interesting thing to note here is
performed before, during and after orthodontic treatment
that another membrane bond molecule and its
with fixed appliances. Comparison of CT examinations
binding ligand OPG (osteopotegerin) can develop
permits three-dimensional evaluation of osteoclastic
to block RANK ligand and prevent osteoclast
and osteoblastic periodontal remodelling. The picture
formation .5
showed orthodontically induced bone dehiscence that
Kanzaki and Chiba et al have demonstrated in the was partly repaired by osteoblastic periodontal
rat experiments that local OPG gene transfer to remodelling in the retention period.
periodontium inhibits OTM. Research of this kind
As we apply orthodontic force on the tooth, following
may be an exciting thing in future to block the tooth events at the microscopic level occur, based on current
movement specifically at a particular site during the
understanding.
course of OTM.6. It is also shown in the same
experimental study that exogenous injection of PGE 2 Primarily, alteration in the blood flow which results in
increases RANKL mRNA expression in POL cells in reduced oxygen level at compressed area, and there
rats. might be an increased oxygen level at tension side.
4.5. Apart from the above three cells of bone; we also Secondly, generation of Piezo electric signal, which
have osteoprogenitor cells and bonelining cells. is now stated more appropriately as bioelectric
156
It has been proved that ce lls in POL such as fibroblasts
and bone ce lls such as osteoblasts possess receptors for
these substances, and all these are highly interacting
11
:"·~1~: l o E
~ their adjacent Matrices. These interactions lead to
I transient increase in the intracellular levels of second
- "',' r=:l
.
messengers 2 such as CAMP (Cyclic Adenosine
MQnophosphatel, CGMP (Cyclic Guanosine
_ ..11 ,,1',11 ! Monophosphate), IP3 (Inositol phospatase), Ca+, etc.,
these second messengers advance signals to the nucleus
through series of kinases. In the nucleus of each cell ,
different second messengers account for the differential
patterning, protein synthesis and Gene expression. Such
ne urotra nSm ist l / r
substa nce p, recently identified Immedi ate Early Gene expression
PCs Cytokines [lEG] transcription factors include Cfos, Cjon mRNA,
Leucotrins Calcium
c ha ne l±
egr-I, SPl growth differentiation factor 9B and
Ce ll s extracellular GLA protein. The transcription factors
seems to increase when ce lls are exposed to mechanical
Elevation
messe ngers
]nd stimulation, cytokines and growth factors. 5 ,B These
transcription factors ca n produce either cellular
iCAMP proliferation or cellular differentiation leading to
iCCMP ~ osteoblastic bone formation or osteoclastic bone
i IP3 -..,..~ A9l:'ances signals to resorption.
-..,.. U Nucleus
. The above stated cascade of events, in fact, may be a
Gene transc ription factors released brief summary of current understanding of whole lot of
Cfos mRNA, Cjun, egrl , Ap-I , SP- I
growt~diffe re nti at ion factor 9B, complex activities and interactions occurring in the POL
Cytokinin, GF's and alveolar bone after the application of primary
Produces ce llul ar pro li feration stimulus such as mechanical force or action of hormones.
Fig, 1: Cascade of Histological events during Orthodontic In the next part, we will analyze certain important
tooth Movement. modes of actions of chemical mediators and their
comp lex, internal interactions.
potential in the form of small voltage of curre nt, is
re leased due to bending of bone and deformation of Role of Prostaglandins in Mediating OTM
crysta l structure,
Prostaglandins are synthesized from fatty acids by a
Thirdly, neuro transmitters (examples Substance P, Microsomal enzyme complex (PG synthetase) found in
Vasointestinal polypeptide VIP, calcitonin gene related all Mammalian tissues. 9 In Humans, the most abundant
peptideCGRP) are possibly released on account of precursor is Arachidonic acid, which is present in
physical distortion imposed by peripheral forces on membrane phospholipids of cells. Arachidonic acid
paradental tissues such as nerve fibers and terminals. can be released either by phospholipidases activated
by direct cellular damage or by any nondestructive
ifhus, the primary stimulus such as that of the orthodontic perturbation of the membrane, be it physical, chemical,
orce may elicit its response to cells of POL and bone hormonal or neurohormonal. Prostaglandins can also
n the form of release of be termed as local hormones functioning to co-ordinate
effects of those other hormones which induce
) Bioelectric signals produced on account of bone
prostaglandin synthesis and Prostaglandins function
bending, ' .
through G-protein linked receptors to elicit their cellular
) C hemi ca l mediators such as prostaglandins,
effects.
cytokines, Nitric oxide (NO) etc.,
) Release of neurotransmitters.
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J Ind Orthod Soc 2006; 39:155-164
t
MECHAN ICAL
H ORMONAL Cytokines and growth factors iri OTM
PATH OLOGICAL LipoOxygenase pathway
IPHOSPHOLI PID I ELECTRI CAL I ARACH IDONTIC ACID I The early phase of OTM involves an acute inflammatory
of cell membra nee Phospholipase A Unsaturated fatty ac id I leucolri nes response characterized by periodontal vasodilatation
and migration of leukocytes out of POL capi lIaries. The
Undergows oxygenation by
m icrosomak cyclo orygenase released inflammatory mediators such as Prostaglandins
NSAID' S CAN BLOCK HERE
and interleukins (IU-1 interact with bone ce lls .
Cytokines secreted by leukocytes may interact directly
with bone cells or indirectly, via neighboring cells, such
as monocytes/macrophages, lymphocytes and
fibroblasts, through their production of cytokine, or a
variety of Growth factors. 2,20 Cytokines released have
enzyme
endoperoxide
reductase
multiple activities, which include bone remodeling,
bone resorption and new bone deposition.
Klein and Riasz in 1970 reported first time the Growth Factors are also released during inflammation
involvement of Prostaglandins in OTM.lO After that, and repair by the cell s of POL and bone. Another theory
many in vivo and invitro animal experiments have been states that the growth factors may be secreted by bone
conducted mainly by Oavidovitch and Shanfeld et cells and stored (bound to bound matrix). They are likely
al ll ,12,13 in 1980-83, Yamasaki et aj1 4, (first reported human to be released and activated during bone resorption 24 .
These Factors include fibroblast Growth Factor (bFGF
study) 1982-83, Lee.W et al 15 1990, J. Liker 16 1995,
Selinkale et al 17 2004 and many others. All these and a FGF ), Insulin like Growth Factors (lGF - I, IGF-
II), Transforming Growth Factor ~ (TGF ~), Platelet Growth
experiments indicate a very vital role of prostaglandins
Factor (POGFS) and Bone Morphogenic Proteins (BMP)
in OTM.
IGF- I and IGF-II have been shown to increase Type-I
In the Indian context only one human study and second
collagen and matrix synthesis by osteoblasts. FGF are
of its kind in the world was reported by Anand K. Patil
known to stimulate replication of both osteoblasts and
et al wherein Prostaglandin E2 in lesser dosage of 3IJg
progenitor population. 24
along with Lingnocaine as a vehicle was injected distal
to the Canine in 14 Orthodontic patients. 18 BMP's are now showing promising results in Periodontics
in the field of POL tissue reconstruction. BMP - 2 has
Studies indicate that Prostaglandins increase the number
been shown to induce mesenchymal progenitors to
of Osteoclasts as well as stimulate Osteoblastic cell
differentiate into both osteoblasts and chondrocytes.
differentiation and new bone formation. 2, 19, This is
BMP -2 also has been shown to stimulate committed
specifically true with invitro studies involving PGE 2.
osteo-progenitors (ROB - C 26 cells) to differentiate
into more mature osteoblasts. 25
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Application of small bending forces to bones is known The Stretch activated ion channels are shown to allow
to produce flow of interstitial fluid through the passage of cations ie. Calcium and potassium. Paul.
ca nalicular network, generating streaming potentials. A.G.and Louis Norton 28 , in the University of
The in vitro and in vivo experiments of Cowin et a12 6 Connecticut, have shown that continuous mechanical
1991, and Weinbaum et al 31994, indicate that load similar to an orthodontic force affects the mechano
osteocytes are more sensitive to mechanical stress than sensitive ion c hannels of osteoblastic cells in culture,
osteoblasts, which in turn are more sensitive than thereby producing large increase in intracell.ular
fibroblasts. calc ium. It has been suggested that ion channels may
be linked to cytoskeleton , and are opened when their
In vivo studies conducted in Amsterdam Dept. of Oral cytoplasmic tail is phosphorylated.
cell Biology, Academic Centre for Dentistry, indicate
that application of forces to bone results in several Extracellular Matrix and Cytoskeleton
potential stimuli to bone cell function, including time Reorganization
dependent changes, hydrostatic pressure, direct cell
stra in, fluid flow induced shear stress and electric fields The principle elements of ECM of either PDL or the
res ulting form electrokinetic effects accompanying bone may be considered as collagen fibrous network
fluid flow 27 . providing structural support embedded in and interacting
with a non collagenous matrix consisting of
These events effect osteocytes, which are proteoglycans and various glycoproteins. The
mechanosensor cells of bone .These in turn, activates macromolecules, which make up the ECM, include
osteoblasts or osteoclasts to produce adaptive bone collagen and glycose aminoglycans, These macro
remodeling. These events are depicted in the following molecules are secreted at local levels by cells,
schematic diagram. particularly fibroblasts in the PDL and osteoblasts in
the bone. The matri x metallo proteins (MMPS) represent
Activation of Ion channels major class of enzymes responsible for ECM
Ion channels are tunnel shaped proteins that cross the metabolism 30 •
width of cell membrane, and serve as selective The growth and repair of co nnective tissue is a
conductive pathways for ions that cross the membrane delicately balanced process of ECM removal and
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J Ind Orthod Soc 2006; 39:155-164
replacement, with significant control by MMP and play an important role in adhesion of osteoclast to the
primary natural inhibitors or Tissue inhibitors of metallo bone surface 3 '.
proteinases (TIMPS).
Integrins are found to regulate signaling' pathways by
Cytoskeleton represents a framework attaching cell to changing intracellular calcium, regulatihg incitol lipid
cell or cell to extracellular matrix, thereby presenting turnover, and phosphorylation of intracellular proteins.
a possibility of transducing mechanical forces acting The individual binding of Integrins to osteoclasts and
on the cells or on their adjacent matrices. osteoblasts has been elucidated with the use of cell
adhesion assays, monoclonal antibodies (MABS) and
affinity chromatography. The receptor binding site (RGD)
arginine-glycineaspartic acid was first defined. Similarly
RGES (arginine glycine glutamic acid) receptor binding
site was also identified . In an engineered experimental
study, it was found that both RGES and RGDs bind to
osteoblasts .
Fig. 4: Schematic diagram of Microscopic section, showing In an experimental study, agents such as echistatin, an
Cytoskeleton framework- present among PDL and RGD containing peptide, derived from snake venom
Bone cells and short RGD peptides injected during the experimental
tooth movements in rats have been shown to interfere
with aspects of INTEGRIN mediated signals transduction
There are two types of cellular adhesions possible in
and ultimately to affect bone remodelling. Echistatin
the cytoskeleton framework. One is cell to cell adhesion
can induce disruption of cell matrix interaction and
and the other is cell to ECM adhesion. It is now clearly
appears to cause an early reduction of PP12S FAK
demonstrated histologically that any cytoskeleton
phosphorylation. This results in the disassembly of actin
framework has three main components i.e. Microtubuls,
cytoskeleton adhesion. The total effect of echistatin
microfilaments and intermediate filaments 2 •
attributed to decrease in osteoclast function and
The major subunit protein of the microfilaments is osteoclast numbers. It is also demonstrated by C. Dolce
actin. There are, however many associated protein such et al in an experimental study on rats that orthodontic
as myosin, tropomyosin, vinculin and talin. The cell tooth movement can be completely blocked out at
membrane integral proteins are also identified as cell specific sites by local administration of echistatin or
surface receptors termed INTEGRINS which span the argenine glycine aspartic acid RGD peptide32 . This can
cell membrane from cytoplasm to extra cellular matrix. be of clinical relevance in orthodontic practice in future.
These Integrins mediate cell to cell attachment or cell Production of second messengers
attachment to ECM molecules such as fibronectin
laminin and talin. It has also been shown that actin As we understand , the primary stimulus or first
and vinculin bind to this talin integrin complex .. messenger may alter activity through cell membrar;le.
The responsive cells possess receptors on the cell
Integrins when analyzed at molecular levels, are a membrane for these substances. Their interactions lead
family of alB heterodimeric cel l surface receptors, to increase in intracellular levels of second messengers.
composed of at least fourteen distinct a sub units and The production of second messengers such as CAMP -
eight or more 13 - subunits that can associate non co- and CGMP - during Orthodontic force was demonstrated
valently in various combinations. Osteoblasts have been way back during 1973-76 by Davidovitch and Shanfeld ll ,
shown to express the I ntegri n a2 131 and as 131. 12, 13 in series of animal experiments.
160
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Patil et al
The intramembranous components that have been shown early and in the later phases of orthodontic tooth
to playa vital role in production of CAMP are Ca+ ions movement cycle 5, 33
and ce ll membrane enzymes. CAMP is known to
activate Protein Kinase - A, enzymes responsible for A study conducted at the center for craniofacial and
protei n phosphorylation. molecular biology, University of California by H.B .
Moon et al has demonstrated that more than 130 genes
CAMP response is also modulated by Prostaglandins. were regulating orthodontic tooth movement up or down
The response of increase in intracellular CAMP levels after one day of application of orthodontic force in mice
ca n be inhibited by Ibuprofen a drug commonly used experiments. Among them were several transcription
as pain killer, and many other NSAIDS. and growth factors such as SP1, growth differentiation
9B, myogenic factors as well as extra cellular matrix
Inositol phosphate is another second messenger, which GLA protein 34
is also similar in its production as that of generation of
CAMP2. Inositol phosphate in presence of phospholipase Clinical application of knowledge of
gets converted to phosphotidylinositol biphosphate OP). histological aspects of orthodontic tooth
Phospolipase then cleaves IP 2 into Inositol Triphosphate movement
OP 3) and Diacyl glycerol with subsequent release of
ca lcium from intracellular stores. The calcium thus Clinical application of chemical mediators of OTM has
released is responsible for Protein Phosphorylation in been a subject of great interest to all orthodontists.
nu c leus. The Diglycerol formed activates protein Research in the field of orthodontics is now mainly
Kinase C. This protein Kinase C is an enzyme focused on biology of orthodontic tooth movement.
responsible again for Protein phosphorylation. Advanced molecular biology and genetic engineering
have opened wide scope in this particular aspect of
Now the research is focused on how this mechanical orthodontics. Enhancing rate of tooth movement
strain ultimately influences the biochemical reactions pharmaco-therapeutically or electrophysio logically or
within the nucleus of each cell of PDL and bone. genetically would be an ultimate goal for all present
day researchers.
In the signaling cascade process, receptor activation is
fo llowed by second messenger generation i.e. CAMP Among the chemical mediators affecting orthodontic
and insitol triphosphate . They advance signals to the tooth movement, Prostaglandins (PGs) head the li st.
nu c leus through series of kinases. In the nucleus,
different second messenger account for the differential History of PGs dates back to 1939 with their discovery
pattern, Immedi ate Early Gene expression (l EG) or also by Von Euler from human semen. It was in 1970 that
termed as third messengers. This transcription of lEGs Klein and Riasz reported first time that PGs are
i.e. C-fos gene, C-jun gene and egrnl -gene has been important mediators of OTMl O. A series of in vivo and
shown to be influenced when exposed to cytokines, in vitro experiments there after have been reported,
growth factors or mechanical stimulation. These since the initial experiments by Zeev Davidovitch 11 ,12,
transcription factors released, depending on presence 13 and Yamasaki et al 14. Following, this many in vivo
of various stimuli, can either produce cellular and in vitro studies have been reported in the literature
proliferation or differentiations. 15,16,35,36,37,38,39
In rat experiments, it was shown that within three hours But till now only, two human studies have been reported.
of applying orthodontic force there was an increase of First study was by Yamasaki et ai, wherein a total of
1.7 fold in C-fos mRNA expression, when compared to 40IJg of PGE1, was injected in the vestibular region at
respective controlled side where no orthodontic tooth the upper right canine area during orthodontic tooth
movement was app li ed. At 24 hours after initial movement. The results of this particular clinical
orthodontic force application, significant induction of experiment showed almost twice faster orthodontic
1.9fold was detected. Final 1.5 fold induction was seen tooth movement on the PGEl injected side as compared
after 7 days of force application .. These results show a to non-injected side of canine retraction l4.
peak of C-fos induction in cyclic fashion i.e. at 3 and
24 hours and at 7 days after appliance activation. The The other experimental studies listed above mainly
authors speculate that C-fos may playa role in both conducted in animals by various authors, have shown
161
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[DoS J Ind Orthod Soc 2006; 39:155-164
'-'
increased tendency of root resorption with exogenous From these above studies, one can deduce certain merits
application of PGs. The tendency for root resorption is and demerits involving the clinical application of
dose dependent. As the PG dosei ncreases root resorption prostaglandins.
tendency also increases. J. Leiker has suggested
application of minimal dosage of PGs (1-3~g) in animal The prostaglandins have definitely shown increased tooth
experiments during orthodontic tooth movement with movement when injected or systemically administered.
no root resorption tendency1 6.
The disadvantages of injection mode of prostaglandins
Another human study was reported by Anand K. Patil, as reported on animals or human experiments include:
S.D. Gaitonde et al. This was the second human trial potential risk for root resorption when used in higher
till date l 8. In this study, 1 ~g/ml PGE 2 (along with doses, associated pain and inflammation, and leakage
lignocaine as vehicle) was injected in the vestibular of drug at the site of injection resulting in anchor loss.
region on the right side of the upper quadrant in 14
An interesting study reported by Massound Seifi et ai,
patients during separate canine retraction stage on the
wherein the injection of PGE2 was supplemented with
1st, 3 rd , 6 th day. Left side was the control side with
oral administration of calcium in rats during OTM. This
injection of plain lignocaine. The total dosage of PGE 2
study indicates no tendency for root resorption 38.
used in this study was only 3~g. The 60 days of post
canine retraction results showed a one and half times Ali Reza Sekhawat et al have reported a study involving
more increased tooth movement on the prostaglandin oral administration of stable PGEl analog such as
E2 injected side. No macroscopic/roentgenographic misoprostol during orthodontic tooth movements in rats.
side effects were observed throughout the experimental They reported that oral misoprostol can be used to
procedure. enhance orthodontic tooth movement with minimal root
resorption 37.
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