REVIEW ARTICLE

M Yamaguchi RANK ⁄ RANKL ⁄ OPG during orthodontic

tooth movement

Author's affiliation: Structured Abstract

M. Yamaguchi, Department of Orthodontics, Author – Yamaguchi M
Nihon University School of Dentistry at
Objectives – Orthodontic tooth movement is induced by mechanical stimuli and
Matsudo, Chiba, Japan
facilitated by remodeling of the periodontal ligament (PDL) and alveolar bone. A
Correspondence to: precondition for these remodeling activities, and ultimately for tooth displacement,
Masaru Yamaguchi
is the occurrence of an inflammatory process.
Department of Orthodontics
Nihon University School of Dentistry at Materials and Methods – This review covers current knowledge regarding the role
Matsudo of the receptor activator of nuclear factor-kappa (RANK), receptor activator of
2-870-1 Sakaecho-Nishi nuclear factor-kappa ligand (RANKL), and osteoprotegerin (OPG) in periodontal
Matsudo City
tissue reactions, in response to orthodontic forces.
271-8587 Chiba
Japan Results – It has been found that concentrations of RANKL in GCF increased during
E-mail: yamaguchi.masaru@nihon-u.ac.jp orthodontic tooth movement, and the ratio of concentration of RANKL to that of OPG
in the GCF was significantly higher than in control sites. In vivo studies have shown
the presence of RANKL and RANK in periodontal tissues during experimental tooth
movement of rat molars, and that PDL cells under mechanical stress may induce
osteoclastogenesis through upregulation of RANKL expression during orthodontic
tooth movement.
Conclusions – Considering the importance of RANK, RANKL, and OPG in
physiologic osteoclast formation, it is reasonable to propose that the
RANKL ⁄ RANK ⁄ OPG system plays an important role in orthodontic tooth movement.

Key words: orthodontic tooth movement; RANK ⁄ RANKL ⁄ OPG; periodontal

ligament; cytokines

Introduction

Orthodontic tooth movement is induced by mechanical stimuli and

facilitated by remodeling of the periodontal ligament (PDL) and alveolar
bone. A precondition for these remodeling activities, and ultimately for
tooth displacement, is the occurrence of an inflammatory process.
Dates: Vascular and cellular changes were the first events to be recognized and
Accepted 5 February 2009 described, and a number of inflammatory mediators, growth factors,
To cite this article: and neuropeptides have been demonstrated in periodontal supporting
Yamaguchi M:
tissues. Their increased levels during orthodontic tooth movement have
RANK ⁄ RANKL ⁄ OPG during orthodontic tooth
movement led to the assumption that interactions between cells producing these
Orthod Craniofac Res 2009;12:113–119 substances, such as nerve, immune, and endocrine system cells,
Copyright  2009 The Author.
regulate biologic responses following the application of orthodontic
Journal compilation  2009 Blackwell Munksgaard forces (1).
Yamaguchi. RANK ⁄ RANKL ⁄ OPG

Mechanical stress evokes biochemical responses and source of the aqueous component of GCF; however, the
structural changes in a variety of cell types in vivo and gingival tissue through which the fluid passes, along
in vitro. The overall objective of many investigations with bacteria present in the tissue and gingival crevice,
has been to further understanding of the mechanisms can modify its composition (5). With constituents of
involved in converting molecular and ⁄ or mechanical GCF being derived from a variety of sources, including
stress to the cellular responses resulting in tooth microbial dental plaque, host inflammatory cells, host
movement. In sites at which inflammation and tissue tissue, and serum, GCF varies according to the condi-
destruction have occurred, cells may communicate tion of the periodontal tissues. In addition to the cells,
with one another through the interaction of cytokines immunoglobulins, microorganisms, toxins, and lyso-
and other related molecules. Thus, it is important to somal enzymes detected in GCF, the mechanism of
more completely elucidate the complex cytokine bone resorption may also be related to the release of
cascade flow associated with inflammation-mediated inflammatory mediators present in GCF. Recently, a
tissue destruction at the molecular level (2). number of GCF constituents have been shown to be
The role of the receptor activator of nuclear factor- diagnostic markers of active tissue destruction in peri-
kappa (RANK), receptor activator of nuclear factor- odontal diseases (6), although only a few studies have
kappa ligand (RANKL), and osteoprotegerin (OPG) focused on those involved in bone remodeling during
system in inducing bone remodeling was recently orthodontic tooth movement. Mogi et al. (7) found that
demonstrated. The tumor necrosis factor (TNF)-related GCF concentrations of IL-1b and IL-6 were significantly
ligand, RANKL, and its two receptors RANK and OPG, higher in a group with severe periodontal disease
have been shown to be involved in this remodeling compared with controls, and Yavuzyilmaz et al. (8)
process (3). RANKL is a downstream regulator of demonstrated the GCF IL-1b and TNF-a levels had a
osteoclast formation and activation, through which positive correlation to mean pocket depths, suggesting
many hormones and cytokines produce their osteo- that the cytokines may be involved in the pathogenesis
resorptive effect. In the bone system, RANKL is of periodontal diseases. Further, Mogi et al. (9) reported
expressed on the osteoblast cell lineage and it exerts its that an increased concentration of RANKL and
effect by binding to the RANK receptor on osteoclast decreased concentration of OPG were detected in GCF
lineage cells. This binding leads to rapid differentiation from patients with periodontitis, while the ratio of
of hematopoietic osteoclast precursors to mature RANKL concentration to that of OPG in GCF samples
osteoclasts. OPG is a decoy receptor produced by was significantly higher for patients with periodontal
osteoblastic cells, and competes with RANK for RANKL disease than for healthy subjects. Taken together, these
binding. The biologic effects of OPG on bone cells data suggest that RANKL and OPG contribute to
include inhibition of terminal stages of osteoclast osteoclastic bone destruction in periodontal disease.
differentiation, suppression of activation of matrix Storey (10) proposed that the early phase of tooth
osteoclasts, and induction of apoptosis. Thus, bone movement involves an acute inflammatory response
remodeling is controlled by a balance between RANK– characterized by periodontal vasodilation and migration
RANKL binding and OPG production (4). This review of leukocytes out of the capillaries. Recent research has
covers current evidence regarding the role of the led to the hypothesis that inflammatory mediators are
RANK ⁄ RANKL ⁄ OPG system in periodontal tissue reac- released following mechanical stimulus, triggering the
tions, in response to orthodontic force application. biologic processes associated with alveolar bone
resorption and apposition (2). Among the local bio-
chemical mediators are cytokines secreted by mono-
Gingival crevicular fluid study during nuclear cells and leukocytes. Cytokines can provoke the
orthodontic tooth movement synthesis and secretion of numerous substances that
form the molecular basis for cell-to-cell communication,
Gingival crevicular fluid (GCF) is an osmotically medi- including prostaglandins (PGs) and growth factors, thus
ated inflammatory exudate found in the gingival sulcus, interacting directly or indirectly with bone cells (2).
where it tends to increase in volume with inflammation Uematsu et al. (11) found that the levels of inflammatory
and greater capillary permeability. Serum is the primary mediators (IL-1b, IL-6, TNF-a, epidermal growth factor,

114 Orthod Craniofac Res 2009;12:113–119

 Yamaguchi. RANK ⁄ RANKL ⁄ OPG

and b2 microglobulin) in GCF were elevated during periodontal tissues during experimental tooth move-
orthodontic treatment, and Grieve et al. (12) reported ment of rat molars. Therefore, it is suggested that in
similar results for PGE and IL-1b. Further, Lowney et al. response to mechanical stress, RANKL is regulated by
(13) described an increase in TNF-a in GCF from teeth inflammatory cytokines in the PDL.
undergoing orthodontic forces. As noted above, inflam- The number and distribution patterns of RANKL and
matory mediators have been detected in GCF samples RANK-expressing osteoclasts change when excessive
during orthodontic tooth movement in the early phase. orthodontic force is applied to periodontal tissues.
Nishijima et al. (14) found an increased concentration of Aihara et al. (21) and Kim et al. (22) showed the pres-
RANKL in GCF during orthodontic tooth movement, and ence of RANKL in periodontal tissues during experi-
the ratio of concentration of RANKL to that of OPG in the mental tooth movement of rat molars. Kanzaki et al.
GCF was significantly higher than in control sites in (23, 24) demonstrated that transfer of the RANKL gene
another study. Further, Kawasaki et al. (15) reported that to the periodontal tissue activated osteoclastogenesis
the age-related decrease in amount of tooth movement and accelerated the amount of experimental tooth
may be related to a decrease in RANKL ⁄ OPG ratio in GCF movement in rats. In contrast, OPG gene transfer
during the early stages of orthodontic tooth movement. inhibited RANKL-mediated osteoclastogenesis and
Consequently, analysis of GCF samples may provide a inhibited experimental tooth movement. Therefore, it
better understanding of the biochemical processes is suggested that PGE2, inflammatory cytokines, and
associated with tooth movement, potentially helping the RANKL–RANK system may be involved in regula-
clinicians make therapeutic choices based on qualitative tion of orthodontic tooth movement (Fig. 1).
and quantitative information.

In vitro study in response to mechanical

In vivo study during orthodontic tooth forces
movement
The PDL lies between hard tissues cementum and
In in vivo studies, experimental tooth movement has alveolar bone where it functions as a cushion to with-
been shown to lead to significantly increased recruit- stand mechanical forces applied to teeth, thus it
ment of cells that belong to the mononuclear phago- receives and responds to external forces. It is likely that
cytic system. Saito et al. (16) indicated that there was a PDL cells stimulated by forces of mastication, occlusal
local increase in PGs in the PDL and alveolar bone contacts, and orthodontic treatment produce local
during orthodontic treatment, and other studies have factors that participate not only in the maintenance
shown an arrest in tooth movement in experimental and remodeling of the ligament, but also in the
animals when non-steroidal anti-inflammatory drugs metabolism of adjacent alveolar bone.
were administered (17). Further, when PGE1 was In vitro studies have shown that the expression and
administered locally or systemically to rats, accelerated production of some inflammatory mediators (PGE2,
bone resorption, and tooth movement were observed IL-1b) are promoted by mechanical stimulation of the
after the application of orthodontic forces (18). There- PDL (25). COX-2 is induced in PDL cells by cyclic
fore, PGs have been shown to play an important role in mechanical stimulation and is responsible for the
orthodontic tooth movement. augmentation of PGE2 production in vitro (26). In
Macrophages have the ability to produce cytokines, addition, Kanzaki et al. demonstrated that compressive
such as IL-1b and IL-6, levels of which are known to force upregulated RANKL expression and induced
increase during orthodontic tooth movement (16). The COX-2 expression in human PDL cells in vitro. Nakao
number and distribution patterns of RANKL- and et al. (27) reported that intermittent compressive forces
RANK-expressing osteoclasts change when excessive induced RANKL in PDL cells via IL-1b. Compression
orthodontic force was applied to periodontal tissue, force significantly increased RANKL and decreased
and IL-1b and TNF-a were expressed in osteoclasts in OPG secretion in human PDL cells in a time- and
pathologic status rat periodontal tissues (19). Shiotani force–magnitude-dependent manner (14, 28). Further,
et al. (20) have also shown the presence of RANKL in Nakajima et al. (29) reported that in response to

Orthod Craniofac Res 2009;12:113–119 115

Yamaguchi. RANK ⁄ RANKL ⁄ OPG

Fig. 1. Immunohistochemical staining for

RANK, RANKL, and OPG in the PDL for days
1–7 of orthodontic tooth movement. Osteo-
clastic activity indicated by arrows. Scale
bar = 50 lm.

compression force the production of RANKL increased Several investigations have been conducted on the
via FGF-2 expression. These results suggest that PDL effects of low-energy laser irradiation on bone tissues
cells under mechanical stress may induce osteoclasto- and these may relate to potential applications in
genesis through upregulation of RANKL expression orthodontic tooth movement. Saito and Shimizu (47)
during orthodontic tooth movement. reported the stimulatory effects of low-energy laser
irradiation on bone regeneration in the median pala-
tine suture area during rapid maxillary expansion in
Low-power laser irradiation stimulates the rats. Ozawa et al. (48) demonstrated that laser irradia-
velocity of tooth movement via the tion stimulates cellular proliferation and differentiation
RANK ⁄ RANKL ⁄ OPG system of osteoblast lineage nodule-forming cells, especially in
committed precursors, resulting in an increase in the
From the patientÕs point of view, accelerating tooth number of differentiated osteoblastic cells as well as in
movement would be desirable during orthodontic bone formation. Kawasaki and Shimizu (49) reported
treatment to reduce treatment duration. Literature that low-energy laser irradiation stimulated the amount
shows various methods to stimulate bone remodeling of tooth movement and formation of osteoclasts on the
such as drug injections (30), electric stimulation (31), pressure side during experimental tooth movement
and ultrasound application (32). Recently, various bio- in vivo. Further, Fujita et al. (50) and Yamaguchi et al.
stimulatory effects of low-energy laser irradiation have (51) demonstrated that low-energy laser irradiation
been reported in wound healing (33–35), fibroblast (36, enhanced the velocity of tooth movement via
37), and chondral (38) proliferation, collagen synthesis (RANK) ⁄ RANKL and the macrophage-colony stimulat-
(39–41), and nerve regeneration (42). Acceleration of ing factor and its receptor (c-Fms) expression.
bone regeneration by laser treatment has been the Together, these findings suggest that low-energy laser
focus of recent studies (43, 44). In the field of ortho- irradiation accelerates bone remodeling and thus could
dontics, low-energy laser irradiation has been utilized potentially shorten the orthodontic treatment period.
for several types of clinical orthodontic treatment, such
as reduction of post-adjustment pain (45), or treatment
of traumatic ulcers in the oral mucosa induced by an Root resorption and the
orthodontic appliance (46). However, scant informa- RANK ⁄ RANKL ⁄ OPG system
tion is available concerning the effects of low-energy
laser irradiation on bone remodeling during ortho- Many orthodontists consider external apical root
dontic tooth movement. resorption (EARR) to be an unavoidable pathologic

116 Orthod Craniofac Res 2009;12:113–119

 Yamaguchi. RANK ⁄ RANKL ⁄ OPG

consequence of orthodontic tooth movement. EARR is

often considered an iatrogenic disorder that occurs
unpredictably with orthodontic treatment. This un-
desirable side-effect has been described as being the
outcome of a sterile, complex inflammatory process
that involves various disparate components including
mechanical forces, tooth root and bone tissues, cells of
the surrounding matrix, and certain known biologic
messengers (52). Killiany (53) reported that EARR of
>3 mm occurs at a frequency of 30% in a patient
population, while 5% of treated individuals have
>5 mm of root resorption. Harris et al. (54, 55)
reported that the sum of the effects of the patientsÕ sex, Fig. 2. Schematic representation of events related to inflammation in
periodontal ligament when stimulated by orthodontic forces.
age, severity of the malocclusion, and the kind of
mechanics applied accounted for little of the overall
variation in EARR. polymorphism in allele 1 and EARR. Low et al. (61)
Orthodontic force applications induce a local pro- reported that RANK and OPG regulated the root
cess that includes all of the characteristics of inflam- resorption process, while Yamaguchi et al. (28) re-
mation (redness, heat, swelling, pain, and altered ported that the compressed PDL cells obtained from
function). The inflammatory process, an essential patients with severe EARR produce a large amount of
feature of tooth movement, is actually the funda- RANKL and upregulate osteoclastogenesis. Therefore,
mental component behind the root resorption process evidence suggests the occurrence of orthodontic root
(56). The process of resorption requires specific resorption involves a combination of genetic factors
interactions between various inflammatory cells and and RANKL (Fig. 2).
hard tissues, whether bone, cementum or dentine,
and is a multistep process. The underlying cellular
processes involved in root resorption are thought to Conclusion
be similar if not identical to those occurring during
bone resorption (57). Multinucleated clast cells are The multifunctional roles of RANK, OPG, and RANKL
formed as a result of cellular injuries to bone, may provide an important link between bone remod-
cementum, or dentine (58). The progenitor cells arrive eling, orthodontic tooth movement, and root resorp-
at the resorption site via the bloodstream as mono- tion to other local and systemic conditions.
nuclear cells (derived from hemopoietic precursors in
the spleen or bone marrow) and fuse prior to getting
involved in the resorptive process. The pathogenesis Clinical relevance
of this process has been assumed to be the removal
from the PDL of necrotic tissue compressed by an Recent studies show that orthodontic forces change
orthodontic load. It is believed that PGs are intimately the levels of OPG, RANK, and RANKL in GCF during
involved in root resorption (59). orthodontic tooth movement. The rate of orthodontic
A search for risk factors affiliated with the develop- tooth movement is significantly increased by the
ment of EARR during orthodontic treatment has led to transfer of RANKL gene. It has also been reported
the suggestion that individual susceptibility, genetics, that the compressed PDL cells in cases of severe
and systemic factors may be significant modulators of EARR may produce a large amount of RANKL, and
this process. Current research on orthodontic root upregulate osteoclastogenesis. Therefore, the RANK ⁄
resorption is directed toward identifying genes involved RANKL ⁄ OPG system may provide an important link
in the process, their chromosome loci, and their pos- between bone remodeling, orthodontic tooth move-
sible clinical significance. Al-Qawasmi et al. (60) re- ment, and root resorption during orthodontic tooth
ported evidence of a linkage disequilibrium of IL-1b movement.

Orthod Craniofac Res 2009;12:113–119 117

Yamaguchi. RANK ⁄ RANKL ⁄ OPG

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