R E V I E W A R T I C L E
Modulators for orthodontic tooth movement
Ridhima Seth
Department of Dental Sciences, Kurukshetra University, Kurukshetra, Haryana, India
Abstract
Background:
Orthodontic tooth movement (OTM) is an interaction between the
mechanical forces applied on the tooth and the response of biological tissues of the
oral cavity to those forces. Bone has the ability of self-repair as well as it can adapt to
changes in the mechanical needs of the body. The triggering factor for OTM is a strain
on the periodontal ligament (PDL). Mechanical forces applied in orthodontic treatment
cause the physical distortion of PDL and alveolar bone cells resulting in activation of
inflammatory pathways, such as the prostaglandin pathway. Osteoclast formation has
seen to be increased after the activation of T-cells, whereas the food derivatives such as
sulforaphane and natural isothiocyanate are observed to promote osteoblastic activity.
However, these agents get flushed by blood circulation rapidly. Although, there is a
possibility that the agents that enhance bone formation and bone resorption can accelerate
tooth movement and shorten the time of orthodontic therapy.
Aim:
The objective of the
review is to highlight the inflammatory process involved in the orthodontic treatment as
well as bone remodeling, ultimately to understand how modulation of the inflammatory
process of the immune system with the help of external agents can enhance the OTM.
Conclusion:
The advantages of inflammatory mediators can be utilized in orthodontic
therapy that can give a novel perspective to orthodontic treatment. However, this demands
a thorough understanding of the biology of oral tissues at cellular as well as molecular
level as our knowledge is limited in this perspective. Therefore, more studies and research
work should be motivated in the field of oral biology to bring better treatment outcomes
in less amount of time.
Clinical
Significance:
The understanding of concepts related to
inflammatory processes as well as bone remodeling will help us to develop modulators in
future that will resolve the problem of extended treatment time involved in orthodontic
treatment. Hence, the knowledge of cellular biology can be applied to make orthodontic
more efficient by reducing the treatment time as well as events of relapse.
Keywords: Bone remodeling, immune response, inflammatory mediators, modulators, orthodontic tooth movement, periodontal ligament
Correspondence
Dr. Ridhima Seth, Kurukshetra University, Kurukshetra, Haryana, India. E-mail: [email protected]
Received 21 May 2019; Accepted 30 August 2019
doi: 10.15713/ins.ijcdmr.143
How to cite the article:
Seth R. Modulators for orthodontic tooth movement. Int J Contemp Dent Med Rev, vol.2019, Article ID: 061219, 2019. doi: 10.15713/ins.ijcdmr.143
Introduction
Orthodontic tooth movement (OTM) is the movement of a
tooth under the influence of mechanical forces. The orthodontic
forces are the intentional forces applied to the teeth to move
them in a particular direction. OTM demands the presence of
a functional and healthy periodontal ligament (PDL).
[1,2]OTM
differs appreciably from physiological tooth movement and
movement of teeth at the time of the eruption. Physiological
tooth movement is characterized by the displacement of teeth in
the buccal direction into the cancellous bone as seen as a result
of growth into cortical bone.
[3]The orthodontic movement is
uniquely characterized by the sudden creation of compression
and tension regions in the PDL.
[4]The triggering factor for OTM is a strain on the PDL,
eventually on the bone-related cells as well as the extracellular
matrix. This strain subsequently leads to multiple changes in
gene expression in these cells as a result of interactions between
cells and the extracellular matrix. Consequently, it leads to
the activation of a variety of cell-signaling pathways, which
ultimately leads to stimulation of PDL to initiate the process of
bone resorption and deposition.
to reduce treatment time is by use of low friction and
self-ligating brackets,
[6,7]preformed robotic archwires,
[8,9]and use of
microimplants.
[10,11]Other methods focus on increasing the velocity of OTM
by enhancing the bone remodeling. These methods include
use of biochemical agents, mechanical, or physical stimulation
of the alveolar bone that involves the use of cyclic vibration,
[12]magnets,
[13]or direct electrical current,
[13]and surgical
interventions to accelerate tooth movement.
[14]Therefore, the
researchers are inclined to developing the least invasive methods
that enhance the OTM as well as cause minimal side effects to
the patients.
[15]The processes involved in OTM can be modulated by
systemic as well as local application of medications by a
stimulatory or inhibitory effect. The commonly used are dietary
supplements, such as vitamins and minerals.
[15-18]Bone
Bone is a dense connective tissue, and the bone matrix is
mineralized fibrous tissue. The minerals embedded in the
matrix of bone provide the compressive strength, and the fibers
provide adequate tensile strength.
[19]Bone has the ability of
self-repair as well as it can adapt to changes in the mechanical
needs of the body.
[20]Osteoclasts are large multinuclear cells,
about 50–100
µ
m in diameter and have the function to break
down bone tissue with the help of enzymes. Osteoclasts are the
exocrine cell that dissolves bone minerals and enzymatically
degrade extracellular matrix of bone. They are derived from
hematopoietic stem cells of the body. The mononuclear
osteoclasts adhere tightly to a bone and fuse with each other into
multinucleated osteoclasts.
[21]The remodeling process helps the
bone to adapt to changes in long-term loading.
[22]Bone remodeling
Bone remodeling is a continuous process of the body under
normal conditions. Bone remodeling helps the bone to maintain
its volume as well as its strength to meet the physiological
demands of the bone.
[23]The “pressure-tension theory” that is
associated with OTM states that the application of physiologic
force, whether compression or tension resulting in changes
in the PDL space activates mesenchymal stem cells. As a
result, the progenitor cells in the PDL that experience force
will differentiate into compression associated osteoclasts
and tension-associated osteoblasts, causing bone resorption
and apposition, respectively.
[24]Mechanical forces may cause
hyalinization that leads to necrosis in the PDL, resulting in bone
resorption. Hyalinization can be defined as cell-free areas in the
PDL wherein the standard tissue architecture, as well as the
staining characteristics of collagen in the processed histologic
material, are lost.
[25]Types of tooth movement
Common types of tooth movements are tipping, bodily
movement, rotation, and intrusion/extrusion movement.
Tipping is considered the most natural type of tooth movement.
It results when a single force is applied and the tooth tips around
its center of rotation that is located in the middle of the root,
close to its center of resistance.
[19]OTM can be defined as a
response to disturbance in the physiological equilibrium of
the dentofacial complex by external forces.
[17]To explain the
biological response, two theories have been developed,
pressure-tension theory, and bone bending theory.
[11]Immune response to orthodontic tooth movement
OTM results due to the bone remodeling sequence that is
induced by therapeutic mechanical stress. The mechanical strain
on the tooth is transferred to the PDL and therefore, cells in the
PDL respond to the mechanical stress to regulate the resorption
and formation of the bone matrix by signaling the surrounding
cells.
[26]The Osteoclasts on the compressed side of PDL of the
tooth resorb the alveolar bone.
[16,27,28]Bone bending theory is based on the assumption that
deformation in the alveolar bone is the primary cause of bone
remodeling, so the pressure state (positive or negative) of the
bone matrix is the first stimulus to differentiate apposition and
resorption in overloaded conditions. Whenever the orthodontic
appliance is activated, forces delivered to the tooth are transmitted
to all tissues around the force application.
[19]Another outcome
of the physical distortion by forces on the paradental tissues is its
effect on peripheral nerve fibers and terminals. Neuropeptides
stored in nerve terminals within the PDL either may be released
into the extracellular space as the applied stress persists or stream
toward the ganglion.
[29]Molecular basis of bone remodeling
Many genes are involved in osteoblast differentiation. The
transcription factor (TF) Cbfa1 (or Runx2) is one of the
most specific bone formation markers that control osteoblast
differentiation.
[24]Role of inflammation in tooth movement
Inflammation is described as a protective response to insult
with pathogens, injury, or foreign bodies encountered by
host tissues. The process of inflammation is characterized by
vascular dilation, enhanced permeability of capillaries, increased
blood flow, and leukocyte recruitment. Polymorphonuclear
neutrophils are the first cells to reach the inflamed site.
[30]The
bioactive lipid mediators, primarily eicosanoids, are involved
in pathophysiologic processes, including those associated
with host defense and inflammation.
[17,31,32]Prostaglandins
are chemical messengers that belong to a family of hormones
called eicosanoids. The major types of eicosanoids are
prostaglandins, thromboxanes, and leukotrienes. Prostaglandins
are produced from arachidonic acid in the body, and arachidonic
acid is derived by enzyme phospholipase A2 that acts on
phospholipids containing arachidonic acid.
[33]Prostaglandins
prostaglandin E synthase in leukocytes, whereas prostaglandin
I2 is generated through prostacyclin synthase in endothelial cells
and thromboxanes are made through thromboxane synthase in
platelets.
[35]Leukotrienes are produced by inflammatory cells
such as macrophages and mast cells.
[17]The production of immuno resolvents initiates resolution
of inflammation. The lipid mediators that are synthesized
during the resolution phase of inflammation including resolvins,
protectins, lipoxins, and maresins.
[36]Lipoxins are produced
from endogenous fatty acids, mainly the arachidonic acid. They
have potent anti-inflammatory and resolution actions.
[27,37,38]Lipoxins A4 and B4 are mainly known for their actions like
inhibition of polymorphonuclear neutrophil infiltration and
as stimulation of recruitment of macrophages.
[39,40]Other
immuno resolvents such as resolvins, protectins, and maresins
are derived from dietary fatty acids, essentially
ω
-3 fatty acids
which are commonly derived from fish. Production of resolvin
E1 is shown to be associated with the concentration of aspirin
in plasma, hence results in amelioration of the clinical signs
of inflammation.
[41,42]Similarly, D-series resolvins that are
docosahexaenoic acid-derived resolvins reduce inflammation by
reducing platelet-leukocyte adhesion.
[43]Thus, it is evident that
resolution of inflammation is carried out by protective mediators
that are arachidonic acid-derived lipoxins, aspirin-triggered
lipoxins,
ω
3-eicosapentaenoic acid derived resolvins of the
E-series, docosahexaenoic acid-derived resolvins of the D series,
protectins, and maresins.
[44]Mechanical forces applied in orthodontic treatment cause
the physical distortion of PDL and alveolar bone cells resulting
in activation of pathways, such as the prostaglandin E2 (PGE2)
pathway, that in turn results in structural and functional
changes in the extracellular, cell membrane, and cytoskeletal
proteins.
[25]Cytokines as mediators of mechanically induced bone
remodeling Cytokines 8 are mediators released from cells, which
modulate the activity, of other cells. The first ones identified were
lymphokines produced by lymphocytes, and the term cytokines
are used. Inflammatory cells produce numerous cytokines, which
mediate various stages of inflammation. Some of these cytokines
mainly interleukin–1 alpha, and one beta, tumor necrosis factor,
gamma interferon have been implicated in the mediation of the
bone remodeling process
in vitro
.
[29]The earliest bone resorption marker is the interleukin1
beta (IL-1
β
). PGE2, and interleukin-6 (IL-6) are also other
inflammatory cytokines that can facilitate osteoclastic bone
resorption processes.
[24,45]Osteoblastic cells also control
osteoclastic processes by synthesizing RANKL to promote more
osteoclastic differentiation.
[24,46]Moreover, bone formation
induced by orthodontic forces resulted in increased levels of
ALP were human gingival crevicular fluid supporting the idea
that they might have biological activities in the early stages of
tooth movement.
[18,47]Nitric oxide (NO) is also a crucial regulator of bone
responses to mechanical stress and is produced by the activity
of enzyme nitric oxide synthase (eNOS) or inducible nitric
oxide synthase (iNOS) present in the endothelium. It enhances
bone formation as well as protects osteocytes from apoptosis. It
also helps in osteoclastic activity.
[48]Recent reports proposed a
role for nitric oxide as a marker of vascular signal transduction
during the initial state of orthodontic tooth movement.
[49-51]This
molecule has shown to be a participant in bone remodeling and
the regulation of blood vessels and nerves.
[52,53]Modulators of orthodontic tooth movement
Various new methods are being tried to accelerate OTM to
shorten treatment times as well as to reduce side effects such as
pain, discomfort, and side effects of root resorption resulting in
subsequent development of non-vital teeth.
[5]Numerous reports
have described the pharmacological acceleration of OTM
through the activation of osteoclasts. However, because these
drugs are rapidly flushed by blood circulation, daily systemic
administration, or daily local injection is needed.
[54]Vitamin D
Bioactive 25(OH) D3 and 1,25 (OH)2D3, as well as 24R,25
(OH)2D3 can stimulate osteoblast growth and differentiation
in vitro
.
[55]1,25(OH)2 D3 when administered
in vivo
for 28
consecutive days, increased bone formation and reduced bone
resorption and increased trabecular bone volume in mice.
[56]It
was observed that long-term administration of 1
α
,25[OH](2)-2
β
- (3hydroxypropyloxy)vitamin D3 metabolite (eldecalcitol)
reduced the bone turnover.
[57]It is a steroid hormone having specific receptors in many
organs and tissues. It acts by activating DNA and RNA in the
cells of the target organ to produce proteins and enzymes that
work in the bone resorption process. In particular, the active
form of Vitamin D, 1,25-dihydroxycholecalciferol, is one of
the most potent stimulators of osteoclastic activity known.
[33]Collins and Sinclair,
[58]as well as Kale
et al
.,
[59]have reported that
the local administration of Vitamin D increased the rate of tooth
movement in cats and rats, respectively.
Bisphosphonates
Bisphosphonates antagonize osteoclastogenesis through
various mechanisms of action.
[60]Long-term oral or parenteral
administration of bisphosphonates increases bone mineral
density as well as bone volume, whereas it reduces bone porosity
and risk of fracture. However, bisphosphonate therapy has
side effects. Most common among these is gastrointestinal
intolerance. Moreover, both oral and parenteral administration
of bisphosphonates can lead to osteonecrosis of the jaw.
[61,62]The topical administration of a potent blocker of bone
resorption, bisphosphonate (risedronate), caused a significant
and dose-dependent reduction of tooth movement and inhibited
relapse of tooth movement in rats.
[63]Bisphosphonates selectively
Clodronate is a non-N-containing bisphosphonate that
contains two chlorine atoms in its side-chain. As a result of its
structural similarity to pyrophosphate, it is known to inhibit
osteoclast function.
[65]The local administration of clodronate did not cause any
visible inflammatory reactions at the injection site or any
systemic side effects, such as loss of appetite or change in
body weight. The local administration of clodronate caused
a significant reduction in tooth movement in the third phase,
which is considered to be due to bone resorption by osteoclasts.
This indicates that clodronate inhibits bone resorption induced
by orthodontic mechanical stress.
[66]Tooth movement on the
control side exhibited three typical phases, i.e a period of rapid
change, a lag phase, and a phase of progressive movement.
[67]Prostaglandins
Leiker
et al
.
[68]studied the effect exogenous PGE2 on the rate of
tooth movement in rats. According to his reports, injections of
exogenous PGE2 did enhance the amount of tooth movement.
Kehoe
et al
.
[69]administered misoprostol (100 mg/kg) twice
daily in guinea pigs and noted a significant increase in the degree
and rate of orthodontic tooth movement. In a study by Sekhavat
et al
.,
[70]it was observed that misoprostol enhances tooth
movement in doses as low as 10–25 mg/kg, twice daily, without
increasing the amount of root resorption.
Nonsteroidal Anti-inflammatory Drugs
Cyclooxygenase inhibitors such as indomethacin and other
nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit
prostaglandin synthesis, inhibit the appearance of osteoclasts.
Orthodontic mechanical forces produce inflammation in
periodontal tissues.
[16]According to them, celecoxib suppressed
tooth movement as well as root resorption. On the contrary,
aspirin, acetaminophen, and meloxicam do not seem to affect
orthodontic tooth movement.
[71]Chumbley and Tuncay
[72]showed that indomethacin inhibited orthodontic tooth
movement. Celecoxib and prednisolone have proved to show an
inhibitory effect on osteoclastic as well as odontoclastic activities.
While a low dose of celecoxib decreased tooth movement, it did
not affect root resorption.
[71]Further work by Yamasaki showed
that local prostaglandin injection could also increase the rate of
OTM in primates.
[73]Tetracycline may have a similar potential while presenting fewer
side effects since it can be used in its non-antimicrobial form.
[74]Miscellaneous
Osteoclast formation has seen to be increased after the
activation of T-cells, whereas the food derivatives such as
sulforaphane and natural isothiocyanate are observed to
promote osteoblastic activity through epigenetic mechanisms
by increasing matrix mineralization. The flavonoids stimulate
calvarial osteoblast proliferation and mineralization.
[75]The
other bone protecting agents are the growth factors, such as
BMP, fibroblast growth factor (FGF), and vascular endothelial
growth factor (VEGF).
[76]Substances with Anti-Cathepsin effect
The newly discovered molecule with an antiosteoporotic effect
is the monoclonal antibody against cathepsin K (CTSK).
[77]Cathepsin K is known to be a proteolytic enzyme that degrades
collagen I in the bone matrix and activates bone resorption.
The cathepsin K antibody, due to the coupling between bone
resorption and bone formation, inhibits both these processes,
but more markedly bone resorption and only transiently
bone formation. Long-term administration of cathepsin K
antibodies, such as odanacatib, increased BMD and decreased
the fracture rate.
[78,79]Further non-traditional molecules with
antiosteoporotic potential.
New molecules with anti-sclerostin effects
Subcutaneous administration of monoclonal anti-sclerostin
antibodies, such as AbD09097, stimulates bone formation and
increases bone mass through activation of the Wnt pathway,
independently of bone remodeling.
[80,81]Other non-invasive techniques
Low-level laser therapy
Low-level laser therapy (LLLT) is better called as
photobiomodulation, or biostimulation implicates the
administration of either low levels of red light or near infrared
wavelength to treat a variety of diseases. There are commonly
known as cold laser as it does not increase the local tissue
temperature by more than 1°C42, 43. At the cellular level, LLLT
acts on mitochondria,
[82]which increases adenosine triphosphate
(ATP) production and the induction of TF.
[83,84]The TF stimulate
protein synthesis and lead to cell proliferation as well as migration.
They can also change the levels of cytokines, inflammatory
mediators, and growth factors.
[85]As LLLT accelerates bone
regeneration and remodeling by increasing vascularization,
promoting trabecular osteoid tissue formation, and enhancing
tissue metabolism;
[86]therefore, it was thought to be beneficial also
in the acceleration of orthodontic tooth movement.
[15]Low-intensity pulsed ultrasound
Ultrasound is basically a sound wave that can be transmitted
into biological tissues, and it has a frequency above the limit of
human ear perception, which. It is used in the field of medicine
for diagnostic as well as therapeutic purpose.
[87]In a recent study
conducted on a rat model, LIPUS enhanced the OTM by 45%.
Moreover, it promoted alveolar bone remodeling as well.
[88]Mechanical vibration
can promote bone healing, enhance bone strength, and reduce
the adverse impact of the catabolic process.
[90]It is speculated
that mechanical vibration can reduce the period in the lag phase
during OTM resulting in painless and rapid change.
[91]Conclusion
The discussion in the earlier sections makes it clear that if
the advantages of inflammatory mediators are applied to
orthodontic therapy, keeping the side effects minimal, then it
can bring a new perspective to orthodontic treatment. However,
this requires the extensive knowledge of body system at the
cellular and molecular levels. Moreover, a better understanding
of molecular biology and its consequences on cellular physiology
will help to modulate growth processes and immune responses.
Therefore, it demands robust research in the field of oral biology.
To summarize, research in the field of cellular and molecular
biology is lagging, and enhancement in the field of oral sciences
will help to develop innovative orthodontic therapies that will
correct malocclusions efficiently and with minimal side effects.
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