Biomechanical and Biological Responses of Periodontium in Orthodontic Tooth Movement: Up-Date in A New Decade
Biomechanical and Biological Responses of Periodontium in Orthodontic Tooth Movement: Up-Date in A New Decade
Biomechanical and Biological Responses of Periodontium in Orthodontic Tooth Movement: Up-Date in A New Decade
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Nowadays, orthodontic treatment has become increasingly popular. However, the biological mechanisms of orthodontic tooth
movement (OTM) have not been fully elucidated. We were aiming to summarize the evidences regarding the mechanisms of
OTM. Firstly, we introduced the research models as a basis for further discussion of mechanisms. Secondly, we proposed a new
hypothesis regarding the primary roles of periodontal ligament cells (PDLCs) and osteocytes involved in OTM mechanisms and
summarized the biomechanical and biological responses of the periodontium in OTM through four steps, basically in OTM
temporal sequences, as follows: (1) Extracellular mechanobiology of periodontium: biological, mechanical, and material
changes of acellular components in periodontium under orthodontic forces were introduced. (2) Cell strain: the sensing,
transduction, and regulation of mechanical stimuli in PDLCs and osteocytes. (3) Cell activation and differentiation: the activation
and differentiation mechanisms of osteoblast and osteoclast, the force-induced sterile inflammation, and the communication
networks consisting of sensors and effectors. (4) Tissue remodeling: the remodeling of bone and periodontal ligament (PDL) in
the compression side and tension side responding to mechanical stimuli and root resorption. Lastly, we talked about the clinical
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implications of the updated OTM mechanisms, regarding optimal orthodontic force (OOF), acceleration of OTM, and prevention
of root resorption.
INTRODUCTION were excluded for irrelevance. After reading the full text, 317 of
Orthodontic treatment is aiming to move malpositioned teeth to the remaining 487 articles were excluded because of their low
an appropriate position through the remodeling of the period- quality or lack of relevance. Ultimately, 170 studies were included
ontium stimulated by orthodontic force. The underlying biome- in this review. The reasons for exclusion are noted in the
chanical and biological mechanisms of orthodontic tooth Supplementary materials.
movement are essential for efficient and safe orthodontic
treatment. Since the first publication regarding the mechanism Synthesis of results
of OTM in 1911, several theories had been proposed1. Up to now, According to the results of the entitled studies, 15 studies were
the compression–tension theory is well accepted and proposes related to the different types of research models for OTM
that cellular responses are modulated by chemical messengers, researches and were discussed at first. Totally, 118 studies focused
released from blood flow or cells in situ, in response to mechanical on the exact mechanisms of OTM, including the mechanobiology,
stress imposed on the periodontal ligament and alveolar bone. cytobiology, and immunology of periodontium and osseous
However, the detailed mechanisms of OTM still remain to be tissue, which were divided into four steps for clear logic. Finally,
elucidated. In recent years, abundant new findings related to 37 studies reported the cutting edge developments of OOF,
biomechanical and biological changes in periodontium during acceleration of OTM, and prevention of root resorption, and they
OTM have been published. In this study, we summarized the were synthesized in a section for understanding clinical implica-
knowledge of OTM mechanisms mainly based on studies tions of OTM mechanisms.
published in the past decade, and provided an up-date review
for the new decade, with the focus on sequential biomechanical
and biological responses of the periodontium in OTM, and their DISCUSSIONS
relevant clinical implications. Research models
Generally, there are three categories of experimental models for
investigating biomechanical and biological responses of the
RESULTS periodontium in OTM, including the in vivo, in vitro, and analytical
Study selection models. Different models are used for research purposes, and an
The initial literature search yielded 6 808 papers. 2 863 articles integrative study based on multiple experimental models can
were selected after removing duplicates, in which, 1 946 studies reach more comprehensive and reliable conclusions.
1
State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Orthodontics, West China Hospital of Stomatology, Sichuan
University, Chengdu, China
Correspondence: Jianru Yi ([email protected]) or Yu Li ([email protected])
Vessel
Force on tooth
PDLCs
PDLCs-osteocytes
signaling O2
Osteocytes
Fig. 1 When a maxillary incisor is retracted, the bone resorption (−) Hypoxia Strains on PDLCs Strains on osteocytes
occurs in the compression side and in the labial side of the alveolar
bone, while bone deposition (+) in the tension side and in the
palatal side of the alveolar bone. To explain the mechanism, we T/B cell
hypothesis that the PDLCs and osteocytes are the primary sensors Monocyte Platelets
responding to mechanical signals and the PDLCs control the soft Activation of Activation of
tissue remodeling, while a PDLC-dependent PDLCs-osteocytes Inflammation osteoclasts osteoblasts
signaling network control the internal hard tissue remodeling and
osteocytes control the external hard tissue remodeling
theory called the Biphasic Theory divides OTM into the initial
Catabolic Phase, during which osteoclasts (OC) resorb bone at both ECM synthesis and
compression and tension sites, and the Anabolic Phase, which Bone resorption Bone deposition
ECM degradation
occurs subsequently to restore the alveolar bone to its pretreat-
ment levels. The Biphasic Theory affirmed the fact that the PDL was Fig. 2 The process of the transduction from mechanical loadings to
the primary target of orthodontic force and induced inflammation- biological signals. Step 1: the extracellular mechanobiology of the
periodontium (in yellow). Step 2: cell strains (in red). Step 3: cells
dependent osteoclastogenesis for the Catabolic Phase. The activation and differentiation (in green). Step 4: tissue remodeling
Anabolic Phase is mainly based on the fact that osteoblast (in blue)
activation requires intermittent loads of specific frequency and
acceleration at physiologic levels in long bones and alveolar bone,
while the orthodontic tensile force, which is a static force, causes extracellular matrix (ECM) changes in responding to force in PDL
bone resorption on long bones20. This theory provoked the and alveolar bone, mainly including matrix deformation and the
thinking about the types of force and relative cell responses. To subsequent fluid flow alteration. The neurovascular system
explain the inconsistent phenomenon with OTM that the bone responses were also involved. We emphasized the important role
under loading is osteogenic and under release it is resorptive, there of the PDL and its material properties. In the second step, the
were primarily two explanations described in Wise’s review21. It is mechanical signals were transduced through ECM to the mechan-
obvious that compression force superimposes the tissue injury osensory cells (PDLCs and osteocytes) and activated intracellular
onto the physiological response, which produces resorptive signaling pathways, leading to primary cell responses. Some new
inflammatory products to absorb the injured tissue. It is proved mechanisms including non-coding RNAs, hypoxia, and autophagy
that orthodontic force induces systemic immune responses within were developed in recent years. In the third step, we summarized
periodontal tissues associate with the recruitment of the systemic the regulatory mechanisms of activation and differentiation of OBs
inflammatory monocytes and multiple inflammatory factors22. This and OCs as the basis of PDLCs- and osteocyte-regulated down-
may be the reason why the existence of PDL causes totally adverse stream mechanisms. A network including PDLCs–OBs/OCs,
bone remodeling effects under mechanical force. Another theory osteocytes–OBs/OCs, and PDLCs–osteocytes signaling are the key
proposed that osteoclastic activities at compression sites can be for our hypothesis. In the fourth step, responsive matrix enzymes
considered as a consequence of loss of the functional strain from are secreted, leading to tissue remodeling including synthesis or
the PDL, while osteogenic activities at tension sites can be a result degradation in PDL, as well as deposition or resorption of alveolar
of loading of the PDL fibers. Therefore, the key of this question can bone. The root resorption was also briefly described due to its
be attributed to the existence of the PDL, which senses the inevitable damage during OTM.
mechanical stimuli primarily and initiate downstream signal
responses including cell activities and inflammation. Step 1: extracellular mechanobiology of the periodontium
Based on the progress in the OTM mechanisms, we proposed a Matrix strain and fluid flow. On the histological level, once a force
new hypothetical theory that during OTM, the PDLCs and is applied and the tooth moves, relative to the fixed socket, the
osteocytes are the primary sensors responding to mechanical tooth along with its adjacent periodontium will be compressed on
signals and the PDLCs control the soft tissue remodeling, while a one side and stretched on the other side. On the compression side,
PDLC-dependent PDLCs-osteocytes signaling network controls the the force leads to compression of PDL fibers and subsequently the
internal hard tissue remodeling and osteocytes control the external alveolar bone. On the tension side, the force leads to the stretching
hard tissue remodeling (Fig. 1). Previous critical reviews, such as V. of PDL fibers and the alveolar bone. Both strains cause matrix
Krishnan’ published early in 200923, has divided the process of the deformation and fluid flow alteration in turn. In the alveolar bone,
transduction from mechanical loadings to biological signals into according to the matrix deformation hypotheses, the application of
four steps: (1) matrix strain and fluid flow, which is basically macroscopical compressive force to bone leads to a magnified
regarding the extracellular mechanobiology of the periodontium, local microscopic strain, inducing bone matrix deformation,
(2) cell strain, (3) cell activation and differentiation, and 4) tissue damages, and microcracks. The accumulation of microcracks
remodeling (Fig. 2). In the first step, we mainly introduced the represent the first damage caused by mechanical loads and result
tissues of orthodontic patients and loaded PDLCs53. A static fibers and α-SMA provide the contraction ability of myofibroblasts,
equiaxial strain also activated the expression of ERK1/2 and the which results in tissue contraction. Tenascin-C is another typical
Hippo pathway effector Yes-associated protein (YAP) in strained protein that functions antagonistically to disassemble FADs in order
hPDLCs54. The relationship between potential receptors, ion to avoid overstretching of cells. PDL myofibroblasts were also
channels and signal pathways mentioned above may be valuable reported to produce collagen and osteocalcin positively, suggesting
objects in further studies, and they are summarized in Fig. 3. that myofibroblasts had the ability to take part in mechanical
It is also suggested that a tension-dependent cellular integrity signal transmission and periodontal tissue remodeling58. The Wnt/
known as “tensegrity” is physiological pre-existing in the cell and β-catenin pathway and transforming growth factor-beta (TGF-β)
directly causes chromatin deformation, consequent regulation of were recognized as the prerequisites of myofibroblast differentia-
transcription and protein production55. In the absence of the tion. Under orthodontic load, increasing expressions of Wnt3α, TGF-
tensegrity, cells often experience apoptosis and are incapable to β1, α-SMA, and tenascin-C in both tension and compression PDL
sense an external loading, while cells are more sensitive to regions were found, along with the stimulation of myofibroblast
mechanical loading when the magnitudes of external and internal differentiation by TGF-β159. YAP is a mechanical sensor and a
strains are similar56. The reason is that cell strains will cause cytoskeletal signal mediator in the nuclear, whose target gene is
isometric strain intracellularly, which further induces configura- TGF-β1. The further study found that extracellular mechanical
tional changes of ECM proteins, generating a positive feedback loadings induced the cytoplasmic RhoA/ROCK pathway and the
loop23. Intracellular strain is able to promote assembly of focal intranuclear YAP accumulation, to activate TGF-β1 and RUNX2
adhesion proteins and clustering of integrins, induce configura- transcription, followed by the differentiation from PDLCs into
tional changes of some cytoskeletal proteins, and finally control myofibroblast60. In conclusion, myofibroblast is a newly discovered
gene expression by influencing intracellular signaling pathways. cell taking part in OTM and it was potential to be one of the targets
Therefore, external force and internal actin cytoskeletal contractile in regulating mechanical signal transduction and tissue remodeling.
force are both required for efficient transduction from mechanical Its differentiation sources and process, signal transduction mechan-
to biological signals. isms and functional differences, and commonalities with other
PDLCs are worth investigating.
Myofibroblast. In recent years, myofibroblasts were found to be
differentiated from fibroblasts and exist in the PDL both in vivo and Mechanical signal transduction in osteocytes. Osteocytes were
in vitro under tensile loadings, along with the upregulation of the traditionally considered to be inactive bone matrix placeholder
alpha-smooth muscle actin (α-SMA)57. α-SMA is a mechanosensitive cells and their mechanosensory properties which regulate OBs
protein located in the stress fibers. The synergic effect of stress and OCs functions are taken into account nowadays. The ablation
Osteocyte
Fibroblast M-CSF
RANKL
OSCAR PIRA TREM-2 SIRPβ1
RANK
PI3K PLCγ
Mono-nuclear OCL
IκB
M-CSFR
MAPKs Akt Ca2+
NFκB
Monocyte
NFATc1 TRAP MMP9 CTSK
receptor RANK, initiating the intracellular recruitment of TNF through the MAPK/ERK signaling107. IL-1α was found to be one of
receptor-associated factors (TRAF), among which TRAF6 plays the the most abundant cytokines on the compressed side during the
most critical role. TRAF6, in turn, acts through the inhibitor of NFκB initial stages of OTM, while IL-1β expression significantly increased
(IκB) which generally sequesters and inhibits the NFκB transcription from the 7th day to the 14th day108. Compressive force and IL-1ß
and the IкB kinase (IKK) which modulate phosphorylation of IκB98. induced overexpression of COX-2 gene expression in hPDLCs
OPG, another product of OB and B cell, is a member of the TNF in vitro109. Recently, exosomes from PDLCs stimulated with cyclic
receptor superfamily with 380-amino acid, acting as a decoy stretch suppressed IL-1β production by macrophages, indicating the
receptor for RANKL through its four cysteine-rich domains99. Upon important role of IL-1 in cell-to-cell communication in the PDL under
activation, NFκB drives the expression of NFATc1, the major mechanical loading. And IL-1 may be a great target for clinical
modulator of osteoclastogenesis, and consequently enhances intervention110. In-vitro and in-vivo studies have demonstrated that
transcription of OC differentiating markers including cathepsin K IL-6 could be produced by OBs and fibroblasts in periodontal tissues,
(CTSK), MMP9, and tartrated resistant acid phosphatase (TRAP)100. In inducing bone resorption alone and in concert with other bone-
addition, RANK signals to GRB2-associated binding protein 2 (GAB2) resorbing agents at the early phase of OTM within 24 h111.
and Src family kinase, to activate PI3K/Akt signaling101. Notably, Glycoprotein 130 (gp130) is the central player of the receptor
both M-CSFR and RANK could mediate NFATc1 via the activated complex formed by IL-6–type cytokines during the activation of the
PLC-PKC pathway and increased intracellular Ca2+ concentra- IL-6 signaling pathway. It plays an important role in the formation of
tions102. PLC-related, but catalytically inactive protein (PRIP) was IL-6 binding sites by associating with the IL-6/IL-6R complex in the
previously identified as a novel inositol 1,4,5-trisphosphate-binding transduction of the IL-6 signal. Janus kinase (JAK) activation by
protein with a domain organization similar to that of PLCδ but gp130 results in activation of the signal transducers and activators of
lacking phospholipase activity. PRIP stimulates osteoclast differen- transcription STAT1 and STAT3 and the SHP2/Ras/MAPK signaling
tiation through calcium-calcineurin-NFATc1 signaling via regulating pathway. Liu et al observed enhanced expression of IL-6 and its key
intracellular Ca2+ 103. However, its upstream regulators were unclear. signaling factors gp130, STAT3, and SHP2 protein and mRNA at the
Additionally, some other co-stimulatory pathways regulating tension and compression sides of the teeth in a mice OTM model,
Ca2+ release were found. These pathways are mediated by the indicating the special role of IL-6 in the bone remodeling process112.
OB-associated immunoglobulin-like receptor (OSCAR), paired IL-8 is secreted by monocytes and its expression induced by the
immunoglobulin-like receptor A (PIRA), triggering receptor initial orthodontic force on the first day significantly increased in
expressed on myeloid cells 2 (TREM-2), and signal-regulatory protein the tension side, stimulating RANKL expression to regulate bone
β1 (SIRPβ1)104. OSCAR and PIRA bind to intracellular Fc receptor resorption113. The combination of mechanical vibration and
gamma chain (FcRγ), while TREM-2 and SIRPβ1 interact with DNAX- compressive force upregulated RANKL/OPG, COX2/PGE2, IL-6, and
activating protein 12 (DAP12)105. FcRγ and DAP12 both contain IL-8 mRNA, and protein expression in isolated PDLCs, indicating the
immune receptor tyrosine-based motifs (ITAM), which are phos- synergistic effect of several inflammatory factors during OTM114.
phorylated and activate spleen tyrosine kinase (Syk) and phospho- Orthodontic forces also resulted in increased levels of IL-17 and IL-23
lipase Cγ (PLCγ) in turn, which induces the release of Ca2+106. in the gingiva crevicular fluid (GCF), which were statistically
The process discussed above is shown in Fig. 4. significant at 7 days of force application at compression sites in
orthodontic patients115. However, we do not know the exact effect
Cytokines involved in osteoclastogenesis. Members of the IL family on them.
play major roles in the osteoclastogenesis regulations. IL-1, produced Tumor necrosis factor (TNF), primarily produced in α and β forms
by macrophages in α and β forms, has been demonstrated as by monocytes, macrophages, and OBs, can directly bind with the
capable of stimulating the c-Fos and NFATc1 expression in OC TNF receptor-1to induce RANK expression of OC precursors, and
MSC
Osteoblast Immature
Mature osteoblast Osteocyte
progenitor osteoblast
Runx2
Induce
Inhibit
Adipocyte
induce RANKL expression of osteocytes by increased sclerostin Runx2 is classified by different N-termini into two isoforms: the
expression116,117. Several cytokines have interaction effects with TNF type I Runx2 transcribed from the proximal promoter and type II
and collectively constitute a cytokine regulatory network of TNF- Runx2 transcribed from the distal promoter. Both Runx2 types
induced osteoclastogenesis. For example, TNF-α enhanced IL-6 and have similar functions in chondrocytes and OBs. Runx2 inhibits
IL-1 expression in hPDLCs which in return enhanced the activities of MSCs’ differentiation into chondrocytes and adipocytes and
TNF-α, forming a positive feedback loop118. directs them to preosteoblasts124, which then activates the gene
Chemokines, classified into four subfamilies depending on expression of major ECM protein including the alkaline phosphate
whether the first two cysteines near the N-terminal are separated (ALP), Col1a1, OPN, bone sialoprotein, and osteocalcin125. How-
(CXC, CX3C) or not (CC, C), are essential signals for the chemotaxis ever, overexpression of Runx2 severely inhibits OB maturation and
and localization of circulating hematopoietic cells into tissues. They the differentiation into osteocytes, maintaining a supply of
are synthesized by many cell types including fibroblasts, stromal immature OBs126. Many molecules interact with Runx2 and
cells, endothelial cells, bone cells, mast cells, and leukocytes. regulate its functions. For example, mTOR is regulated by Runx2
Chemokines interact with their receptors to form a complex to phosphorylate Akt for modulating cell proliferation and
network relationship, that is, a chemokine can bind to multiple differentiation in OBs and BMSCs on the tension side during
receptors (CCR), and a receptor can also have multiple chemokine OTM in vivo and in vitro. Aonuma reported that Runx2(+/-) mice
ligands (CCL). CCR1 is expressed in marrow cells and binds to CCL3, exhibited suppressed mTORC2/Akt activity127. P70S6 K as a
CCL5, CCL-7, and CCL9, which are produced by OCs and OBs, and downstream molecule of mTOR is activated by phosphorylation
markedly increased by IL-1α and TNF-α in OBs. All the chemokines and subsequently promotes the synthesis of ribosomal and
directly stimulated the chemotactic recruitment OC formation in translational proteins. The expression of PI3K, Akt, and P70S6K in
marrow cultures through a pathway dependent on the presence of human periodontal tissues during OTM began to increase at
RANKL and were diminished in the CCL3−/− mice during OTM119. 3 days, indicating the PI3K/Akt/mTOR/P70S6K signal pathway was
In addition, the CCR2-CCL2 axis is positively associated with the involved in OTM101. The role of mTOR pathways participating in
recruitment and formation of OCs during OTM, but the mechanism the regulation of osteogenesis worth further study and it may be
is still unclear120. On the contrary, CCR5 seems to inhibit OC an important target for pharmacological intervention.
formation in OTM because CCR5-deficient mice have a much Ihh binds to its membrane receptor Patched and relieves the
higher rate of OTM and increased numbers of OCs. At the repression of another receptor Smoothened, ultimately regulating
molecular level, in CCR5−/− mice, OB differentiation markers the transcription factor Gli. Ihh conditional knockout mice using
(Runx2 and OC) and negative OC differentiation regulators (IL-10 Prrx1 promoter Cre transgenic mice, in which Cre is expressed in
and OPG) were significantly decreased compared to wild type, mesenchymal cells in the limbs and calvaria, obtained impaired bone
while cathepsin K, RANKL, and MMP13 were significantly formation and suppressed Runx2 expression phenotype in the limbs.
higher121,122. Recently, therapeutic strategies based on the increase Therefore, Hh signaling is required for OB development. A study
of Atypical chemokine receptor 2 (ACR2), a decoy receptor for CC firstly found Gli1+ cells expressed in PDL which were proliferated
chemokines expressed in OCs and OBs, might be useful to inhibit and differentiated into osteoblastic cells under tensile force and both
bone resorption123. Therefore, chemokines and their receptors are pharmacological and genetic Gli1 inhibition led to arrest of bone
potential therapeutic targets in the future. remodeling. Furthermore, Yap expressed in Gli1+ cells and
decreased after the suppression of Gli1+ cells. Conditional ablation
Activation and differentiation of osteoblast. After that PDLCs of the Yap gene in Gli1+ cells inhibited the bone remodeling as well,
sense the mechanical stimuli, MSCs are activated to differentiate suggesting Gli1+ cells are force-responsive cells128. Whether the Ihh/
into OBs, which specifically express osteocalcin and Runx2. MSCs Gli pathway takes part in the OB differentiation and bone
firstly differentiate into OB progenitors and immature OBs. The remodeling during OTM remains investigated.
immature OBs, which express bone matrix protein (BMP) genes The Wnt/β-catenin signaling pathway also plays a vital role. Wnt3a,
and high levels of OPN, differentiate into mature OBs, which Wnt10b, and Wnt5a were found to be involved in the pathway
express high levels of osteocalcin. Finally, the mature OBs during OTM129,130. The Wnt receptor Frizzled and Wnt coreceptors
transform into osteocytes after being embedded in the bone lipoprotein receptor-related protein 5 (LRP5) and LRP6 collectively
matrix. Runx2/mammalian target of rapamycin (mTOR), Indian form a ternary receptor unit at the cell membrane. Stimulating
Hedgehog (Ihh)/Gli, Wnt/β-catenin, and Hippo/Yap pathways are signals activate the T-cell factor and transcription factors lymphoid
the most essential pathways for OB differentiation (Fig. 5). enhancer factor via the unit, upregulating osteogenic genes. The