REVIEW

published: 08 February 2017

doi: 10.3389/fphys.2017.00067

The Potential Use of

Pharmacological Agents to Modulate
Orthodontic Tooth Movement (OTM)
Thaleia Kouskoura 1 , Christos Katsaros 1 and Stephan von Gunten 2*
1
Department of Orthodontics and Dentofacial Orthopedics, School of Dental Medicine, University of Bern, Bern, Switzerland,
2
Institute of Pharmacology, University of Bern, Bern, Switzerland

The biological processes that come into play during orthodontic tooth movement (OTM)
have been shown to be influenced by a variety of pharmacological agents. The effects
of such agents are of particular relevance to the clinician as the rate of tooth movement
can be accelerated or reduced as a result. This review aims to provide an overview of
recent insights into drug-mediated effects and the potential use of drugs to influence
the rate of tooth movement during orthodontic treatment. The limitations of current
experimental models and the need for well-designed clinical and pre-clinical studies are
also discussed.
Keywords: orthodontics, orthodontic tooth movement, tooth movement, pharmacology, pharmacological agents
Edited by:
Giovanna Orsini,
Università Politecnica delle Marche,
Italy INTRODUCTION
Reviewed by:
During orthodontic treatment, the application of sustained force on teeth sets in motion processes
Harald Osmundsen,
University of Oslo, Norway
that ultimately lead to alveolar bone remodeling. These biochemical processes involve a multitude
Victor E. Arana-Chavez, of cellular and molecular networks (Ren and Vissink, 2008; Zainal Ariffin et al., 2011; d’Apuzzo
University of São Paulo, Brazil et al., 2013; Patil et al., 2013). Pharmacological agents have the potential to interfere with the
*Correspondence: biochemical processes which govern tooth movement during, and stability after, orthodontic
Stephan von Gunten treatment. As a result, the possibility to accelerate/enhance OTM where needed (such as in areas
[email protected] of space closure) and to halt tooth movement where desired (to provide anchorage or to ensure
positional tooth stability during the initial retention period) has attracted considerable interest in
Specialty section: the field. Already in 1982 Yamasaki et al. showed that local administration of prostaglandins E1 or
This article was submitted to E2 accelerated experimental tooth movement in monkeys (Macaca fuscata) (Yamasaki et al., 1982).
Craniofacial Biology and Dental In the present article we review reported experimental results on drugs that can modulate
Research,
orthodontic tooth movement (OTM) and discuss the potential of pharmacological strategies aimed
a section of the journal
Frontiers in Physiology
at supporting orthodontic interventions.
Received: 17 October 2016 Molecular Players Involved In Orthodontic Tooth Movement (OTM)
Accepted: 24 January 2017 A necessary prerequisite for selecting, designing and testing suitable molecules to influence OTM
Published: 08 February 2017
is a detailed knowledge of the role of the different cellular and molecular components driving the
Citation: biological process of OTM.
Kouskoura T, Katsaros C and von
To achieve OTM, mechanical forces are applied on teeth. This initially causes fluid movement
Gunten S (2017) The Potential Use of
Pharmacological Agents to Modulate
within the periodontal ligament (PDL) space and distortion of the PDL components (cells,
Orthodontic Tooth Movement (OTM). extracellular matrix, and nerve terminals), setting into motion the process of release of a multitude
Front. Physiol. 8:67. of molecules (neurotransmitters, cytokines, growth factors, arachidonic acid metabolites etc.)
doi: 10.3389/fphys.2017.00067 which initiate alveolar bone remodeling (Krishnan and Davidovitch, 2006).

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Kouskoura et al. Pharmacological Agents and Tooth Movement

Orthodontic load strains nerve endings present in the PDL. subsequently induce osteoclast terminal differentiation possibly
These release in response a number of neuropeptides (substance through their action on RANK and RANKL expression (Taddei
P, vasoactive intestinal polypeptide, and calcitonin gene-related et al., 2012). Another chemokine ligand expressed in the
peptide-CGRP), which act on capillaries and cause the adhesion PDL under mechanical loading, CCL3, exerts its effects by
and migration of blood leukocytes into the area of compression interacting with chemokine receptors 1 and 5 (CCR1 and
(Krishnan and Davidovitch, 2006). These very active cells release CCR5) present on the surface of osteoclasts and osteoblasts.
signaling proteins (cytokines, growth factors) with a direct The effects of chemokines seem to be of different nature
effect on cells of the periodontium. In addition, local hypoxia depending on the receptor to which they bind, as the CCL3-
(unavoidably caused in areas of compression by occlusion of CCR1 interaction leads to the induction of bone resorption by
the PDL vessels) activates hypoxia-inducible transcription factor osteoclast recruitment, differentiation/activation (Taddei et al.,
(HIF)-1α in endothelial cells and osteoblasts (Dandajena et al., 2013), while the interaction of chemokines with CCR5 inhibits
2012). This leads to expression of downstream genes including bone resorption by increasing the production of signals (such
VEGF (vascular endothelial growth factor) and receptor activator as IL-10 and OPG) inhibitory to osteoclast activation (Andrade
of NF-kB ligand (RANKL), which mediate the recruitment of et al., 2009).
peripheral blood mononuclear cells/osteoclast lineage cells from Prostaglandins and leukotrienes are additional players in the
PDL capillaries and their conversion/activation into osteoclasts, process of tooth remodeling. These molecules are produced
respectively. by enzymatic processing of arachidonic acid, a component
Furthermore, when cells in the periodontium (fibroblasts, derived from phospholipids of cell tissue membranes. They
osteoblasts, endothelial and bone lining cells) are subjected to are locally produced hormones with low serum concentration
mechanical stress they express cytokines, growth factors and (Smith, 1989). Prostaglandin production can be induced by
cytokine receptors. Osteoblasts express IL-1b, IL-6, IL-11, TNFa mechanical stress or by growth factors, hormones and cytokines
and their receptors in response to compressive stress. IL-b shows (such as IL-1, IL-6, and TNF-a) present at the sites of tooth
an autocrine effect and enhances the phenomenon (Koyama movement. Prostaglandins mediate events such as vasodilation,
et al., 2008) plus induces osteoblasts to promote osteoclast inflammatory cell recruitment and also act directly on PDL cells.
activity (through induction of RANKL expression). IL-6 is Prostaglandin E2 (PGE2) is the most widely researched
involved in osteoclast recruitment and differentiation. TNFa PG with respect to OTM. PGE2 is produced mainly by
directly stimulates the differentiation of osteoclast precursors to PDL fibroblasts and osteoblasts (Kanzaki et al., 2002) by the
osteoclasts in the presence of M-CFS (which is a glycoprotein action of the inducible enzyme COX-2 (cyclooxygenase 2), and
produced by fibroblasts and endothelial cells in response to subsequently by a specific synthase enzyme (PGE synthase).
growth factors and cytokines, such as PDGF, FGF, IL-1, and IL- The newly formed PGE2 has different effects depending on
6). IL-11 enhances the expression of RANKL, a key molecule the type of transmembrane receptor to which it binds. PGE2
in osteoclast precursor differentiation, in osteoblasts. In areas can drive RANKL expression in osteoblasts (by binding to the
of tension, growth factors (e.g., TGF-β) and cytokines (e.g., EP2 or EP4 receptors), which subsequently leads to osteoclast
OPG) produced by PDL cells can induce apoptosis of osteoclasts activation (Mayahara et al., 2012), or drive bone mineralization
(Kobayashi et al., 2000) and tip the balance toward bone by osteoblasts when binding to the EP1 receptor (Fujieda et al.,
formation. 1999). In addition, PGE2 has been shown to aid osteoclast
One of the immediate responses of the PDL at sites formation (Collins and Chambers, 1992) or lead to transient
of compression is also the rise in the level of matrix osteoclast inhibition when added to osteoclasts in vitro (Fuller
metalloproteinases (MMPs) which are produced by activated and Chambers, 1989).
fibroblasts. Leukotrienes are also produced through the enzymatic
MMPs either degrade collagen fibers (MMP-1 and MMP-8) metabolism of arachidonic acid by 5-lipooxygenase in many
or eliminate the degraded collagen (MMP-9 and MMP-2) to cells including osteoclasts or leucocytes chemoattracted to areas
allow tooth movement (Lekic and McCulloch, 1996; Cantarella of inflammation. The two leukotrienes shown to be involved
et al., 2006). The degradation of collagen is thought to enhance in tooth movement are LTB4 (leukotriene B4) and LTD4 (a
osteoclast activation, osteoclast migration and adhesion to bone. cysteinyl leukotriene), (Moura et al., 2014). Both leukotrienes
Another very important class of molecules expressed by were found to significantly boost the recruitment and terminal
PDL cells under force application (compression or tension) differentiation/activation of osteoclasts through their effect on
are the chemokines. These are chemotactic cytokines that have cytokine synthesis and in the presence of RANKL.
been recognized as playing key roles in inflammatory processes The induction of osteoclasts is also regulated at various levels
but only recently the role of CC inflammatory chemokines in by inhibitor molecules, such as OPG (whose expression is up-
mechanically-induced bone remodeling is starting to become regulated in cells of the periodontium including osteoblasts
clearer (Andrade et al., 2009; Taddei et al., 2012; Lee et al., under tensile stress possibly through the COX pathway of
2015). In general, chemokines mediate chemotaxis of leukocytes PG synthesis), IL-1RA (a receptor antagonist cytokine which
and bring about cellular differentiation. In the PDL, interaction controls the effects of IL-1), IL-12, and IL-10 (which inhibits
between CCL2 (chemokine ligand 2) and CCR2 (chemokine the RANK osteoclast signaling pathway and other osteoclast
receptor 2) have been found to mediate osteoclast precursor stimulating processes) under low stress conditions (Park-Min
attraction to the sites of orthodontic force application and to et al., 2009). In addition, regulatory T cells by direct contact to

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Kouskoura et al. Pharmacological Agents and Tooth Movement

osteoclasts and through secretion of cytokines such as IL-10 and could be used to modulate bone modeling through PEG2
TGF-β also play a key role in suppressing osteoclastic activity induction and bypass some of the limitations of PEG2 injections.
(Zaiss et al., 2007). Balanced osteoclast activity is necessary to
prevent uncontrollable osteolysis and control bone metabolism Hormones (Parathyroid Hormone,
during OTM. 1,25-Dihydroxycholecalciferol, Relaxin)
An outline of the main cellular and molecular components of Parathyroid hormone (PTH) exerts its effects directly on
OTM is shown in Figure 1. osteoblasts and indirectly on osteoclasts through binding
to the PTH type 1 receptor on osteoblasts, leading to
The Search for Pharmacological Agents to expression of insulin-like growth factor-1 (IGF-1), which
Control Orthodontic Tooth Movement promotes osteoblastogenesis and osteoblast survival, and of
In the last decades an increasing number of pharmacological RANKL, which promotes osteoclast activation. PTH is also likely
agents have been explored aiming at the identification of suitable interacting with bone lining cells promoting early osteogenesis
pharmacological means of accelerating or inhibiting OTM. (Dobnig and Turner, 1995; Esbrit and Alcaraz, 2013)
Experimental evidence is mainly based on in vitro and animal Recombinant PTH is clinically used for the treatment of
studies, and a limited number of case-control clinical studies. In osteoporosis and has been shown to mediate bone anabolic
the next sections, current knowledge on pharmacological agents or catabolic effects depending on the circumstances of
that may accelerate or decelerate tooth movement is discussed administration (Esbrit and Alcaraz, 2013). Intermittent exposure
(Table 1). to PTH seems to increase bone formation, while continuous
and long-term exposure (longer than 1–2 years) enhances bone
Pharmacological Acceleration of OTM resorption. Studies on the effects of PTH on tooth movement
Arachidonic Acid Metabolites point toward a role of intermittent treatment with PTH in
Among the arachidonic acid metabolites, PGE2 is by far the most facilitating bone remodeling/turnover and therefore accelerating
widely tested substance in terms of its capacity to modify OTM. tooth movement. This is possibly occurring by PTH enhancing
Evidence, mainly derived from animal studies, points toward a both osteoblast and subsequently also osteoclast activity (Li
positive effect of PGE2 with respect to enhancing bone resorption et al., 2013). To date there no long-term studies employing local
and accelerating tooth movement (Yamasaki et al., 1982, 1984; PTH delivery that discriminate between effects of PTH on tooth
Leiker et al., 1995; Kale et al., 2004). The few available clinical movement when different protocols are used (short-term vs.
studies are of low quality and involve repeated injections of PGE2 long-term administration and intermittent or continuous mode
and follow-up times of a maximum of 60 days (Camacho and of administration). Some short-term animal studies indicate
Velásquez Cujar, 2014). The mode of application of PGE2 is a that a system of slow, continuous release of PTH in areas of
major limitation as it involves repeated injection (due its short compression is able to accelerate OTM (Soma et al., 1999, 2000).
half-life) in combination with an anaesthetic solution to alleviate 1,25-dihydroxycholecalciferol or calcitriol is the most active
the hyperalgesia caused by injection of PGE2. Potential adverse metabolite of vitamin D and has predominantly anabolic,
effects (e.g., root resorption) linked to long-term administration but also catabolic effects on bone. Furthermore, vitamin D
of PGE2, as required in the context of orthodontic treatment, are also modulates the transcription of genes in immune cells
possible given its mode of action but have not been evaluated so (von Gunten et al., 2013). Calcitriol seems to enhance bone
far. remodeling in a similar way to PTH by enhancing osteoblastic
Specific synthases are involved in the pathway of the synthesis proliferation and function (Reichel et al., 1989), while both PTH
of each type of prostaglandins (e.g., PGE and PGD synthases) and and 1,25-dihydroxycholecalciferol have been shown to stimulate
many of them have been cloned and could provide drug targets PG production in osteoblasts further implicating them in the
for the regulation of the synthesis of specific prostaglandins, such process of OTM (Pilbeam et al., 1989; Klein-Nulend et al., 1991).
as PGE2 in the case of OTM (Forsberg et al., 2000). In addition, Some evidence from animal experiments exists on the effect
it is possible that other PGs such as PGI2 may be involved in of local application of calcitriol on tooth movement (Takano-
bone resorption providing further targets for drugs (Wang et al., Yamamoto et al., 1992; Kale et al., 2004; Kawakami and Takano-
1999). Another obvious group of drug targets are the identified Yamamoto, 2004). During the short experimental time of the
receptors of specific prostaglandins (such as the receptors EP1, available studies there is some evidence that calcitriol enhances
EP2, or EP4 of prostaglandin PGE2) and the design of selective the processes of alveolar bone resorption and formation (bone
agonists can provide pharmacological methods of modifying remodeling) leading to acceleration of tooth movement during
OTM through these receptors. force application (Takano-Yamamoto et al., 1992; Kale et al.,
Intravenous immunoglobulin (IVIg) preparations are 2004), and also enhances bone formation and remodeling after
polyspecific and polyclonal immunoglobulin therapeutic OTM (Kawakami and Takano-Yamamoto, 2004). A clinical study
preparations used as a replacement therapy in immunodeficient testing the effects of systemic application of calcitriol indicated
patients (Grader-Beck et al., 2011; Schneider et al., 2015). These that it may produce some enhancement in tooth movement
IVIg preparations were shown to induce COX-2 mediated PGE2 (Blanco et al., 2001).
synthesis and cytokine production (Trinath et al., 2013; von Relaxin is a peptide hormone with strong effects on collagen
Gunten et al., 2013; Djoumerska-Alexieva et al., 2015). It is turn-over. In vitro studies have suggested that relaxin may
possible that local administration of these IVIg preparations have a direct effect on the PDL by means of decreasing the

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Kouskoura et al. Pharmacological Agents and Tooth Movement

FIGURE 1 | An outline of the cellular and molecular mechanism behind the process of OTM. Potential pharmacological agents that could be used to affect
OTM and their site of action are indicated.

expression and release of collagen type I, increasing expression in animal models by locally altering the concentration of either
of certain MMPs and decreasing the expression of inhibitors OPG or RANKL aiming to enhance or decrease the resorptive
of metalloproteinases (TIMPs), (Henneman et al., 2008; Takano action of osteoclasts (Kanzaki et al., 2004, 2006; Dunn et al., 2007;
et al., 2008, 2009) in PDL cells. Despite increased interest in the Zhao et al., 2012). A local gene transfer method to increase the
potential of relaxin to modulate OTM, effects on tooth movement expression of either OPG or RANKL in periodontal tissues was
and tooth stabilization could to date not be confirmed, neither used in some studies, in which acceleration of tooth movement
clinically (McGorray et al., 2012) nor in animal experiments by gene transfer of RANKL and inhibition by gene transfer of
(Stewart et al., 2005; Madan et al., 2007). OPG were observed. For the short experimental time periods
used, gene transfer is reported to have caused no alterations in
bone metabolism in bones distant from the site of injection (Zhao
Pharmacological Deceleration of OTM
et al., 2012).
OPG and RANKL
Of note is that Denosumab, a humanized monoclonal
The potential use of osteoprotegerin (OPG) to inhibit tooth
antibody against RANKL, has recently been added to the list of
movement and enhance stability, stems from the known
pharmacological agents used to combat osteoporosis but has not
physiological role that OPG plays within the PDL in regulating
been evaluated with respect to OTM (Bekker et al., 2004; Boyce
the bone resorbing activity of osteoclasts. OPG is produced by
and Xing, 2008).
osteoblasts and is a decoy receptor for RANKL which prevents
the interaction of RANKL present on osteoblasts’ surface with its
receptor RANK on osteoclasts. In the absence of RANKL-RANK Bisphosphonates
interactions, the activation, terminal differentiation and survival Bisphosphonates exert a strong inhibitory effect on bone
of osteoclasts are negatively affected. Changes in the ratio of resorption and are successfully used for the treatment of
RANKL/OPG in the PDL can fine-tune alveolar bone resorption. osteoporosis. With respect to the possible effects of different
A number of groups attempted to influence tooth movement bisphosphonates on tooth movement, in vitro studies have shown

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Kouskoura et al. Pharmacological Agents and Tooth Movement

TABLE 1 | Agents with proposed potential of accelerating or decelerating chemokine receptor antagonists, such as Met-RANTES, a
orthodontic tooth movement (OTM). modified methionylated CCL5 molecule, which binds to both
Acceleration of OTM Deceleration of OTM
CCR1 and CCR5 receptors and blocks the physiological signaling
pathway that leads to bone resorption (Proudfoot et al., 1996;
Arachidonic acid metabolites N-acetylcysteine Taddei et al., 2012). Such an intervention could be used to
Cytokines Bisphosphonates (Clodronate, Aledronate) enhance anchorage by preventing the movement of teeth under
1,25-dihydroxycholecalciferol Chemically modified tetracyclines (CMTs) mechanical loading.
RANKL CetylPyridinium Chloride (CPC)
Parathyroid hormone Integrin inhibitors Antibiotics/Antiseptics
Relaxin Osteoprotegerin Chemically modified tetracyclines (CMTs) are derivatives of the
tetracycline groups of antibiotics that lack antimicrobial activity
Compiled from recent original work and reviews, as discussed in this article. RANKL,
and the adverse effects associated with the conventional
receptor activator of NF-kB ligand.
tetracyclines. Their ability to inhibit MMPs and pro-
inflammatory cytokines and their apoptotic effects on osteoclasts
that both aledronate (Kim et al., 2012) and clodronate (Liu initially rendered them attractive therapeutic agents for the
et al., 2006) inhibit the stress-induced up-regulation of key management of chronic periodontitis. The CMTs have been
components crucial for mediating tooth movement. Clodronate shown to modify the COX-2 enzyme leading to inhibition of
was shown to reproducibly inhibit the stress-induced expression PGE2 production (Patel et al., 1999) and represent also potent
of COX-2, PGE2, and RANKL in cultured human PDL-derived inhibitors of MMPs (Marcial et al., 2012). These properties
cells in a concentration-dependent manner (Liu et al., 2006). make CMTs a potentially useful pharmacological agent to inhibit
This action of clodronate is likely to indirectly prevent osteoclast tooth movement in order to control anchorage or enhance tooth
formation and allow osteoclast apoptosis. Kim et al. used stability after orthodontic treatment. Initial animal studies (Bildt
chitosan scaffolds loaded with aledronate to investigate possible et al., 2007) showed that oral administration of CMT-3 (now
effects of this bisphosphonate on osteoblasts and on RANKL- known as COL-3) reduced the rate of tooth movement in rats
induced differentiation of osteoclasts (Kim et al., 2012). They in a concentration-dependent manner. The exact mechanism of
observed concentration-dependent positive effects of aledronate action remains to be elucidated.
on the proliferation, differentiation and activity of osteoblasts, Another antibacterial agent, enoxacin, offers an attractive
and a potent inhibitory effect on osteoclast differentiation. An approach for controlling the resorptive activity of osteoclasts.
interesting aspect of this study was that chitosan aledronate For the resorption of bone mineral, the presence of proton
releasing scaffolds seem to ensure a sustained release of pumps in the ruffled borders of osteoclasts is crucial. To this end,
aledronate for a period of 4 weeks, suggesting that this system osteoclasts have the unique ability to produce increasing amounts
might provide a feasible delivery vehicle for long-term treatment. of vacuolar (V) ATPases (proton pumps) upon their activation.
These V-ATPases are transported through interaction with
Cytokine and Chemokine Receptor Antagonists microfilaments within the cytoplasm to the plasma membrane-
Cytokines are released following mechanical stimulation of cells a unique ability limited to clast cells, thus making the targeting
in the PDL. Their effects on initiating tooth movement are of this process a highly specific means for modulation of tooth
mediated through binding to cytokine receptors on target cells. movement. Enoxacin was first identified by crystal structure-
Decreasing the amount of the unbound cytokines could be a based virtual screening as one of the potential molecules which
possible strategy of reducing tooth movement. This approach was could block the binding site of V-ATPase to actin (Ostrov
taken in two studies examining the effects of systemic application et al., 2009). Such interference would in principle prevent
of soluble cytokine receptors on tooth movement and root transportation of the proton pumps to the ruffled border of
resorption in rodents (Zhang et al., 2003; Jäger et al., 2005). The the osteoclast. In vitro studies confirmed the predicted effect
authors concluded that the administration of soluble receptors to (Ostrov et al., 2009) and animal studies showed that a modified
IL-1 and TNF-a, or their combination, led to reduction in OTM version of enoxasin (bis-enoxacin) with enhanced binding to
in all receptor-treated groups by approximately 50% (Jäger et al., bone selectively inhibited osteoclasts resulting in inhibition of
2005). Furthermore, the number and activity of osteoclasts and tooth movement in rats after 28 days (Toro et al., 2013).
odontoclasts were reduced. There is also some evidence from in vitro experiments that the
Another potential approach is to increase the production well-known antiseptic Cetyl Pyridinium Chloride (CPC) inhibits
of osteoclast inhibitory cytokines such as IL-10 and TGF-β. A RANKL-induced osteoclast formation from bone marrow-
potential compound with its origins in the chinese medicine is derived macrophages possibly by supressing a key event in the
triptolide, which upregulates the production of these cytokines RANKL induced intracellular signaling pathway or by interfering
by regulatory T cells (Xu et al., 2016). A water soluble with M-CFS signaling (Zheng et al., 2013). To our knowledge
compound of triptolide, minnelide, has recently become available potential inhibitory effects of CPC on OTM have not been tested
and is currently used in clinical trials to combat pancreatic to date. Its already approved use in dental medicine due to its
cancer. antiseptic properties renders CPC an attractive agent to test for
A potential pharmacological approach to decrease bone potential beneficial effects on tooth stability after orthodontic
resorption and tooth movement is through the use of specific treatment.

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Antioxidants drug is often used in these models and may not result in effective
The theoretical possibility that antioxidants may interfere with or comparable (species difference) drug concentrations at the site
tooth movement derives from observations that the cellular of orthodontic intervention, (3) the generally small sample sizes
concentration of reactive oxygen species (ROS) increases under used and different ages of animals used, which makes reliable
conditions of hypoxia and mechanical stress in PDL fibroblasts conclusions even in the animal studies impossible to be reached,
and that hypoxia has been shown to lead to the expression of key (4) the lack of longer-term animal studies, which would enable
genes involved in the recruitment and activation of osteoclasts examination of the effects of an agents on tooth movement over
(Janssen-Heininger et al., 2000; Dandajena et al., 2012). Altered a time period and also allow observation of side-effects.
ROS levels also influence the characteristics of immune cells When clinical human studies are conducted, there are obvious
(Wehrli et al., 2014). problems related to ethical and practical issues: (1) recruitment
The effects of antioxidants (either resveratrol or N- of sufficient patient numbers, (2) evaluation of the effect of
acetylcysteine) were tested in a split mouth design in rats individual variation, (3) need for initial dose-response studies
(Chae et al., 2011). The authors reported a significant decrease including measurements to assess the levels of the therapeutic
in tooth movement compared to the control sites following local agent at the sites of interest and measurements of the tissue-level
injection of N-acetylcysteine but not resveratrol. outcomes.
The huge majority of the above mentioned studies have
Integrin Inhibitors employed a systemic administration or local injection of
Integrins are a group of transmembrane glycoproteins, which the pharmacological agents. There is multitude of problems
form heterodimeric units on the membrane of PDL clast cells, associated with these approaches. A systemic administration
such as osteoclasts and odontoclasts (Talic et al., 2004). One of does not ensure a constant delivery of an ideal dose of the
their functions is the adhesion of the differentiated clast cells onto agent in the PDL. As it is not clear how circulating values
specific proteins on bone (e.g., osteopontin) and dentine enabling correspond to the gingival dose and how they fluctuate in time,
them to become polarized and start the bone resorption process, mainly due to degradation of the agent, in many cases a dose
but members of the group mediate other functions such as clast tested in the experimental set-up could have been insufficient to
cell migration, cell differentiation and survival. obtain the desired biologic effect. A more important problem is
Integrin molecules adhere to proteins containing RGD the potential of systemic administration to provoke undesirable
(standing for the amino acids arginine, glycine and aspartate) systemic effects, especially when pharmacological agents lacking
epitopes. Such proteins include osteopontin and bone specificity are used. The mere evaluation of side effects is doubtful
sialoprotein (Miyauchi et al., 1991). This property has been in the current experimental protocols as either the test periods are
exploited and a number of studies have used RGD-containing too short or the experimental protocol has not included specific
peptides as antagonists to prevent integrin function. With methods to evaluate such effects.
respect to tooth movement, based on results from animal Local injection of a pharmacological agent or local gene
models it appears that there is the potential for RGD peptides transfer also come with significant problems. For an intervention
to inhibit tooth movement (Dolce et al., 2003) and also root to be clinically useful, it must be characterized by practicality
resorption (Talic et al., 2006). There is, however, indication in its application (in terms of cost and time) and minimal
from the experimental results that a more detailed knowledge discomfort for the patient. Daily or even frequent invasive
of the function of the different integrin molecules is crucial, as procedures are a major prohibiting factors for clinical
generalized inhibition of integrin function at PDL sites may have application. In addition, during tooth movement different
a multitude of undesirable effects. biological processes take place at distinct sites of the PDL. Bone
Another potential means of exploring the role of RGD resorption and bone formation occur simultaneously at different
peptides and inhibiting tooth movement is through the use of areas of the PDL (areas of compression. vs. areas of tension). The
MMP inhibitor molecules to reduce the production of RGD proteoglycan component of the extracellular matrix of the PDL,
peptides by MMPs in areas of compression (Holliday et al., 2003). a hydrated gel, allows the diffusion of free small molecules (such
This animal study used a general (rather than specific) MMP as drugs, hormones) within the pdl and presents a big challenge
inhibitor, Ilomastat, locally delivered and demonstrated some to the effort of achieving targeted therapeutic interventions
reduction in bone resorptive osteoclast activity. at specific sites (compressions vs. tension). Most of the drugs
used can and will influence both processes and can furthermore
Limitations of the Available Studies influence other physiological cellular functions. The use of
Tooth movement is a complex process controlled by the nature of integrin inhibitors is a good example of that.
the mechanical stimuli, by a multitude of signaling pathways and
influenced by the individual’s genetic make-up (Zainal Ariffin
et al., 2011). Naturally, the huge majority of available in vivo FUTURE DIRECTIONS
experimental evidence derives from animal studies. These have
major limitations which include: (1) the inherently different The Need for the Design of Specific
biology in animals which prevents complete inference of the Pharmacological Agents
effects and the side effects of the pharmacological agents in Targeting key processes in the bone remodeling mechanism
humans, (2) the inability to calculate from animal experiments without other undesirable local side effects precludes a detailed
suitable dosages for clinical testing, as systemic application of the knowledge of the cellular events involved. The selection of

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Kouskoura et al. Pharmacological Agents and Tooth Movement

appropriate targets for the drugs and the design of novel (such as matrix-bound inducible molecules). An ideal
drugs or suitable analogs of naturally occurring molecules with vehicle for drug delivery must be non-toxic/biocompatible
high specificity, is key for clinically successful strategies. The (Démoulins et al., 2013), and be biodegradable (so that
pharmacological agents also need to demonstrate high potency no second procedure for its removal is needed) with a
and efficacy in order to achieve clinically significant differences. suitable half-life and ideally allowing controlled release
The cost implications of the process of designing, testing and and alternating delivery of various pharmacological agents,
eventually obtaining approval for the clinical application of a when desired. A convenient method of application (minimal
potential therapeutic agents need to be carefully considered and surgical intervention) and reasonable cost are also required
kept to the minimum to decrease the eventual cost to the patient. to make its clinical application attractive. Materials that
A very useful approach as demonstrated by the processes that led have so far been experimentally used for the purpose of
to the identification of enoxacin, is to screen already known and delivering drugs to influence tooth movement include
approved molecules for clinical applications. the polymer ELVAX (a non-biodegradable polymer) and
methylcellulose (in injectable, gel formulation). However,
Development of Suitable Vehicles of Drug their use was only tested during experimental periods of short
Delivery and Mode of Administration duration.
Suitable drug delivery materials need to be developed to provide
the appropriate mode of release of pharmacological agents in AUTHOR CONTRIBUTIONS
their active form, that is, at the desired rate and amount for a long
period of time (reflecting the duration of orthodontic treatment All authors contributed to conception, data acquisition, drafted
or retention time). Sustained and low grade prostagladin release manuscript and critically revised the manuscript. All authors
through a suitable delivery system could, for example, be used to gave final approval and agree to be accountable for all aspects of
induce and sustain further endogenous PG production (through the work.
a known amplifying mechanism). This can be used to prolong the
effects of short periods of stress in OTM. FUNDING
It is also important that the drug carriers do not have a
tendency to spread into a larger area from the application Research by SvG is supported by the Swiss National Science
site or that are induced only at areas of bone remodeling Foundation (SNSF) and the Swiss Cancer League.

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Talic, N. F., Evans, C., and Zaki, A. M. (2006). Inhibition of orthodontically Conflict of Interest Statement: The authors declare that the research was
induced root resorption with echistatin, an RGD-containing peptide. Am. J. conducted in the absence of any commercial or financial relationships that could
Orthod. Dentofacial Orthop. 129, 252–260. doi: 10.1016/j.ajodo.2004.11.030 be construed as a potential conflict of interest.
Toro, E. J., Zuo, J., Guiterrez, A., La Rosa, R. L., Gawron, A. J., Bradaschia-Correa,
V., et al. (2013). Bis-enoxasin inhibits bone resorption and orthodontic tooth Copyright © 2017 Kouskoura, Katsaros and von Gunten. This is an open-access
movement. J. Dent. Res. 92, 925–931. doi: 10.1177/0022034513501876 article distributed under the terms of the Creative Commons Attribution License (CC
Trinath, J., Hegde, P., Sharma, M., Maddur, M. S., Rabin, M., Vallat, J. M., et al. BY). The use, distribution or reproduction in other forums is permitted, provided the
(2013). Intravenous immunoglobulin expands regulatory T cells via induction original author(s) or licensor are credited and that the original publication in this
of cyclooxygenase-2-dependent prostaglandin E2 in human dendritic cells. journal is cited, in accordance with accepted academic practice. No use, distribution
Blood 122, 1419–1427. doi: 10.1182/blood-2012-11-468264 or reproduction is permitted which does not comply with these terms.

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