Tooth Movement

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Tooth Movement

Volume Editors

Alpdogan Kantarci Cambridge, Mass.

Leslie Will Boston, Mass.
Stephen Yen Los Angeles, Calif.

57 figures, 16 in color, 2016

Basel · Freiburg · Paris · London · New York · Chennai · New Delhi ·

Bangkok · Beijing · Shanghai · Tokyo · Kuala Lumpur · Singapore · Sydney
Dr. Alpdogan Kantarci Dr. Leslie Will
The Forsyth Institute Boston University
Department of Applied Oral Sciences Henry M. Goldman School of Dental Medicine
245 First Street, #6103 Department of Orthodontics & Dentofacial Orthopedics
Cambridge, MA 02142 (USA) 100 East Newton Street
Boston, MA 02118 (USA)
Dr. Stephen Yen
University of Southern California
Herman Ostrow School of Dentistry
Department of Orthodontics, Oral Surgery and
Basic Sciences
Los Angeles, CA (USA)

Library of Congress Cataloging-in-Publication Data

Tooth movement / volume editors, Alpdogan Kantarci, Leslie Will, Stephen Yen.
p. ; cm. -- (Frontiers of oral biology, ISSN 1420-2433 ; vol. 18)
Includes bibliographical references and indexes.
ISBN 978-3-318-05479-8 (hard cover : alk. paper) -- ISBN 978-3-318-05480-4
(e-ISBN)
I. Kantarci, Alpdogan, editor. II. Will, Leslie, editor. III. Yen, Stephen, editor. IV. Series: Frontiers of
oral biology ; v. 18. 1420-2433
[DNLM: 1. Tooth Movement. W1 FR946GP v.18 2016 / WU 400]
RK52
362.1976--dc23
2015034833

Bibliographic Indices. This publication is listed in bibliographic services, including Current Contents® and Index Medicus.
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www.karger.com
Printed in Germany on acid-free and non-aging paper (ISO 97069) by Kraft Druck GmbH, Ettlingen
ISSN 1420–2433
e-ISSN 1662–3770
ISBN 978–3–318–05479–8
e-ISBN 978–3–318–05480–4
Contents

VII Preface
Kantarci, A. (Cambridge, Mass.); Yen, S. (Los Angeles, Calif.); Will, L.A. (Boston, Mass.)

Section 1: Biology and Metabolism of Alveolar Bone

1 Periodontal Ligament and Alveolar Bone in Health and Adaptation: Tooth Movement
Jiang, N.; Guo, W.; Chen, M.; Zheng, Y.; Zhou, J.; Kim, S.G.; Embree, M.C.; Songhee Song, K.; Marao, H.F.;
Mao, J.J. (New York, N.Y.)
9 Cellular and Molecular Aspects of Bone Remodeling
Xiao, W. (Beijing/Philadelphia, Pa.); Wang, Y. (Jilin/Philadelphia, Pa.); Pacios, S. (Philadelphia, Pa./
Sant Cugat del Vallès); Li, S. (Beijing/Philadelphia, Pa.); Graves, D.T. (Philadelphia, Pa.)
17 Bone Remodeling Under Pathological Conditions
Xiao, W.; Li, S. (Beijing/Philadelphia, Pa.); Pacios, S. (Philadelphia, Pa./Sant Cugat del Vallès);
Wang, Y. (Jilin/Philadelphia, Pa.); Graves, D.T. (Philadelphia, Pa.)

Section 2: Mechanical Properties of Dentoalveolar Structures

28 Regional Acceleratory Phenomenon
Verna, C. (Aarhus)
36 Tissue Reaction and Biomechanics
Melsen, B. (Aarhus)

Section 3: Orthodontic Tooth Movement

46 Orthodontic Tooth Movement: A Historic Prospective
Will, L.A. (Boston, Mass.)
56 Stability and Retention
Will, L.A. (Boston, Mass.)
64 Neurologic Regulation and Orthodontic Tooth Movement
Kyrkanides, S.; Huang, H.; Faber, R.D. (Stony Brook, N.Y.)
75 Osteoclastogenesis and Osteogenesis during Tooth Movement
Baloul, S.S. (Cambridge, Mass.)

V
 Section 4: Methods to Facilitate Orthodontic Tooth Movement
80 Nonsurgical Methods for the Acceleration of the Orthodontic Tooth Movement
Almpani, K.; Kantarci, A. (Cambridge, Mass.)
92 Surgical Methods for the Acceleration of the Orthodontic Tooth Movement
Almpani, K.; Kantarci, A. (Cambridge, Mass.)
102 PiezocisionTM: Accelerating Orthodontic Tooth Movement While Correcting Hard and Soft
Tissue Deficiencies
Dibart, S. (Boston, Mass.)
109 Corticision: A Flapless Procedure to Accelerate Tooth Movement
Park, Y.G. (Seoul)
118 Photobiomodulation and Lasers
Chiari, S. (Vienna)
124 A Comparison between Osteotomy and Corticotomy-Assisted Tooth Movement
Yen, SL-K (Los Angeles, Calif.)
130 Conclusion and Future Directions
Kantarci, A. (Cambridge, Mass.); Yen, S. (Los Angeles, Calif.); Will, L.A. (Boston, Mass.)

131 Author Index

132 Subject Index

VI Contents
Preface

We are privileged to have this opportunity to tems are not anymore limited to single-molecule
present this volume on the ‘biology of tooth testing only and associations with a physiological
movement’. As the editors of this book, we aimed process. Diseases and functions are related and
to cover various aspects of the biological basis and present a complex network of events, which in-
mechanisms of orthodontic tooth movement and clude genomics, proteomics, lipidomics and tran-
the growing field of accelerated orthodontics. En- scriptomics. In the oral cavity, these events take
hancement of the rate, quality and stability of the place in an environment heavily colonized by the
orthodontic tooth movement has always been the largest body of bacterial species in humans intro-
goal of the practice. Many methods have been ducing the microbiome. Meanwhile, no other
tried over the course of the last few decades with part of the mammalian system has been exposed
some of these techniques resulting in success. to the complex biomechanical forces regulated by
These approaches ranged from biologicals to me- hormones and neurons as in the oral cavity and in
chanical stimulation and to surgical approaches the periodontal ligament. This challenging but
with different invasiveness. The field is now mov- exciting era introduces novel ideas and requires
ing towards accomplishing the ‘acceleration’ with an integration of science and clinical applications.
less invasive or noninvasive methods. While the Orthodontics is certainly not exempt from these
interest grows both at the clinical level and by the innovations; dentoalveolar structures are bathed
industry, the understanding of the biology is in microbes, biomechanics impact almost every
limited. cell type and process, and the clinical outcomes
Valuable information has been gathered by the are determined by the biological variations.
attempts over the past decades where we realized This volume presents a multidisciplinary ex-
that a simple increase in force will result in tooth pertise on a wide variety of processes related to
morbidity and the arrest of tooth migration. An- and involved in orthodontic tooth movement.
other finding was that a multidisciplinary ap- The premise was that by a better understanding of
proach and teamwork were critical for success. the biological structures and the mechanism
New methods have been introduced and widely through which they respond to biomechanical
tested in humans, in animal models and in vitro; forces, one can get a better perspective on the ‘ac-
we have also recognized the importance of the celeration’. Recent data demonstrate that differ-
translation of biological concepts into the clinical ent pathways of activation may be involved in ac-
practice. celerated orthodontic tooth movement compared
The twenty-first century is the era of ‘omics’. to the conventional approaches. It is critical to
Biology and complex interactions between sys- understand which mechanisms are being in-

VII
volved related to the biology and metabolism of The strength of the volume is the body of in-
alveolar bone. The first section in the book focus- ternationally recognized expert contributors and
es on the periodontal ligament as well as cellular their outstanding work. As editors, we highly ap-
and molecular aspects of bone remodeling under preciate those who made this book possible. The
physiological and pathological conditions. The concept of this text was conceived based on the
second section presents the mechanical proper- notion that there is a need for a nontextbook
ties of dentoalveolar structures as the two major compilation of research in accelerated orthodon-
concepts of regional acceleratory phenomenon tics. This field is developing fast, and we are fully
and biomechanics. Third, orthodontic tooth aware that new research will change many para-
movement is discussed from a historical perspec- digms. The goal of this book is to present the re-
tive and as the basis for stability and relapse while cent advances with the hope that future research
emerging concepts of neurological regulation and will take full advantage of the changes in clinical
coupling between osteoclasts and osteoblasts are practice based on the biological bases.
presented. The last section is devoted to the vari-
ous approaches for accelerating the orthodontic Alpdogan Kantarci, Cambridge, Mass.
tooth movement. Each section has been authored Stephen Yen, Los Angeles, Calif.
by experts in this exciting field of great interest for Leslie A. Will, Boston, Mass.
both the academician and the clinician.

VIII Kantarci · Yen · Will

Section 1: Biology and Metabolism of Alveolar Bone
Kantarci A, Will L, Yen S (eds): Tooth Movement. Front Oral Biol. Basel, Karger, 2016, vol 18, pp 1–8
DOI: 10.1159/000351894

Periodontal Ligament and Alveolar Bone in Health

and Adaptation: Tooth Movement
Nan Jiang · Weihua Guo · Mo Chen · Ying Zheng · Jian Zhou ·
Sahng Gyoon Kim · Mildred C. Embree · Karen Songhee Song ·
Heloisa F. Marao · Jeremy J. Mao
Center for Craniofacial Regeneration, Columbia University Medical Center, New York, N.Y., USA

Abstract periodontal disease. There are myriads of de-

The periodontal ligament (PDL) and alveolar bone are scriptive studies of multiple cell types and their
two critical tissues for understanding orthodontic tooth gene expression profiles of the PDL and alveolar
movement. The current literature is replete with descrip- bone, often separately in orthodontics and peri-
tive studies of multiple cell types and their matrices in the odontal research literatures. Matrix synthesis is
PDL and alveolar bone, but is deficient with how stem/ another area of focus of numerous investigations
progenitor cells differentiate into PDL and alveolar bone of the PDL and alveolar bone. Far deficient is our
cells. Can one type of orthodontic force with a specific understanding of how stem/progenitor cells dif-
magnitude and frequency activate osteoblasts, whereas ferentiate into mature cells in the PDL and alveo-
another force type activates osteoclasts? This chapter will lar bone, including fibroblasts, osteoblasts and
discuss the biology of not only mature cells and their ma- osteoclasts [1]. This deficiency applies to not only
trices in the periodontal ligament and alveolar bone, but our understanding in homeostasis, but also as
also stem/progenitor cells that differentiate into fibro- adaptive responses during tooth movement and
blasts, osteoblasts and osteoclasts. Key advances in tooth periodontal disease.
movement rely on further understanding of osteoblast This chapter focuses on three related topics:
and fibroblast differentiation from mesenchymal stem/ (1) fundamental cell and matrix structures of the
progenitor cells, and osteoclastogenesis from the hema- PDL and alveolar bone, (2) PDL and alveolar
topoietic/monocyte lineage. © 2016 S. Karger AG, Basel bone remodeling during orthodontics tooth
movement, and (3) how our understanding of
PDL and alveolar bone stem/progenitor cells may
The alveolar bone, periodontal ligament (PDL) help advance orthodontics. Orthodontic tooth
and cementum are intimately related structures movement is typically divided into three phases
in development and functions. Collectively, they by clinical observation: the initial phase, the lag
form the periodontium that is of critical relevance phase, and the postlag phase [2]. The initial phase
not only to orthodontic tooth movement, but also occurs 24–48 h after force application. The lag
phase lasts multiple days with little tooth move- um cells in the PDL, following amelogenesis. In
ment. The post-lag phase is when clinically no- addition, osteoblasts, osteoclasts and cemento-
ticeable tooth movement is observed. To date, our blasts are present in the PDL and participate in
understanding of how stem/progenitor cells are the homeostasis of the periodontium. The osteo-
involved in orthodontic tooth movement remains blasts and osteoclasts reside in the PDL on the
at an infancy stage. surface of lamina dura and in endosteal surfaces
of the alveolar bone, and are also responsive to
mechanical stresses.
Periodontal Ligament PDL and alveolar bone readily remodel in ho-
meostasis and orthodontic tooth movement. Os-
The PDL connects the cementum to the alveolar teoblasts in the PDL and alveolar bone are re-
bone by bundles of type I collagen named Sharp- placed every few months [10]. Most biological tis-
ey’s fibers. The width of a periodontal ligament in sues adapt and self-renew, serving as an indication
homeostasis is approximately 0.15–0.38 mm, de- that there must be stem cells, which replenish and
pending on the tooth type. The PDL has two pri- replace terminally differentiated cells that period-
mary functions: (1) to transmit and absorb me- ically undergo apoptosis. Stem cells are immature
chanical stress and (2) to provide vascular supply and unspecialized cells that can (1) self-renew
and nutrients to the cementum, alveolar bone and and (2) undergo asymmetrical differentiation:
the PDL itself [3]. The PDL is a connective tissue producing precise copies of stem cells and at the
and shares certain similarities with tendons and same time differentiate into specialized cell types
other ligaments in the appendicular skeleton [4]. such as fibroblasts and osteoblasts. In a develop-
ing embryo, embryonic stem cells can differenti-
Cells ate into every single 200 types of specialized cells
Fibroblasts constitute about 50–60% of the total in the body, and therefore, are called pluripotent
PDL cellularity [5]. PDL fibroblasts consist of stem cells [11]. In the adult, stem cells are likely
multiple subpopulations and thus are heteroge- more restricted and can differentiate into a lim-
neous. PDL cells experience and respond to me- ited number of cell types, but nonetheless, can re-
chanical stresses [6], such as those in orthodon- plenish mature cells that are lost to apoptosis [12].
tic tooth movement. Other PDL cells include Postnatal stem/progenitor cells are more restrict-
macrophages, lymphocytes and endothelial cells ed in the number of lineages that they can differ-
that form the lining of blood vessels [7]. When entiate into. Typically, progenitor cells differenti-
forces are applied to the tooth, PDL fibroblasts ate into only one type of mature cells during
react by activating stretch-sensitive Ca2+-perme- homeostasis.
able channels and increase actin polymerization There are two types of dental stem cells: epi-
and yield a rapid and transient increase in c-fos thelial stem cells and mesenchymal stem cells [13,
expression that in turn stimulates their prolif- 14]. Epithelial and mesenchymal stem cells inti-
eration and differentiation [8]. Activated fibro- mately interact during tooth development: epi-
blasts secrete plasminogen activator as well as its thelial stem cells giving rise to ameloblasts, where-
inhibitor, matrix metalloproteases and their in- as mesenchymal stem cells differentiating into
hibitors, cytokines (PGE-2) and interleukin-6 fibroblasts, odontoblasts, cementoblasts, osteo-
[9]. blasts, and perhaps other cells in the periodontal
The PDL further consists of defense cells such ligament [15].
as macrophages and mast cells. Epithelial rem- Periodontal ligament cells have been stud-
nants of Malassez are descents of dental epitheli- ied for decades, due to their significance in

2 Jiang · Guo · Chen · Zheng · Zhou · Kim · Embree · Songhee Song · Marao · Mao

Kantarci A, Will L, Yen S (eds): Tooth Movement. Front Oral Biol. Basel, Karger, 2016, vol 18, pp 1–8
DOI: 10.1159/000351894
periodontal disease and also orthodontic tooth Alveolar Bone
movement. Dental follicle cells, which originate
from neural crest derived mesenchyme, differen- A better name for the alveolar bone is dental bone
tiate into cells that form the periodontium and or tooth bone, for tooth loss leads to disappear-
are present in the developing tooth germ prior to ance of the alveolar bone. Although the bulk of
root formation [16]. Among fibroblast-like cells the alveolar bone is trabecular bone, it does con-
in the periodontal ligament, stem/progenitor tain a plate of compact bone adjacent to the peri-
cells have been identified [17]. Typically, soft tis- odontal ligament called the lamina dura. The
sue is scraped from the root of an extracted tooth PDL pierces through the lamina dura and an-
and enzyme-digested to release a small number chors to the alveolar bone, with the other end
of cells. Morphologically, it is impossible to sepa- connected to the cementum [22]. The inner (lin-
rate PDL fibroblasts from PDL stem/progenitor gual) and outer (labial) cortical plates are also
cells. Nonetheless, certain PDL cells yield proge- composed of compact bone.
nies upon single cell colony assay and can differ- Alveolar bone is a mineralized connective tis-
entiate into multiple cell lineages in vitro. In sue and consists of mineral tissue, organic matrix
chemically defined culture conditions, specific and water. In the alveolar bone, 23% is mineral-
PDL cells differentiate into cementoblast-like ized tissue; 37% is the organic matrix which most-
cells, adipocytes, and collagen-forming cells. ly is collagen, and the other 40% is water [23].
When transplanted into immune-compromised
rodents, PDL fibroblast-like cells generated a ce- Cells
mentum/PDL-like structure [17]. To date, little is Multiple cell types are responsible for the homeo-
known how PDL stem/progenitor cells respond stasis and functions of the alveolar bone. The
to mechanical forces such as those in orthodontic most obvious cell types are osteoblasts, osteocytes
tooth movement. and osteoclasts. However, other cell types are also
important, including adipocytes, endothelial cells
Fibrous Matrix that form the lining of blood vessels and immune
Collagen fibers, reticulin fibers and oxytalan fi- competent cells such as macrophages.
bers form the PDL fibrous matrix. Collagen ac- Osteoblasts are mononucleated and special-
counts for over 90% PDL fibers. Type I collagen ized cells that are responsible for bone apposition.
fibers in the PDL are 45–55 nm in diameter and Osteoblasts and fibroblasts share a key functional
have somewhat uniform morphology [18]. PDL similarity in that they both synthesize type I col-
fiber bundles are arranged in directions that re- lagen matrix. Osteoblasts, however, distinguish
flect their functional properties. PDL collagen fi- from fibroblasts by expressing Cbfa1 or Runx2
bers grow separately from bone and cementum that is a master switch for the differentiation of
surfaces, and gradually elongate and approximate stem/progenitor cells into osteoblasts [24]. Al-
each other [19]. though myriad genes control the complex process
Upon application of orthodontic forces, PDL of osteogenesis, Cbfa1 or Runx2 is the earliest
nerve fibers release calcitonin gene-related pep- transcriptional factor and signals the initiation of
tide (CGRP) and substance P [20]. CGRP and bone formation [25]. Other osteogenesis genes
substance P serve as vasodilators and stimulate include bone morphogenetic proteins, trans-
plasma extravasation and leukocyte migration. forming growth factor-β, Indian hedgehog and
CGRP has been shown to induce bone formation ostrix [26–29]. Bone is a dynamic tissue and con-
through stimulation of osteoblasts and inhibition stantly remodels by osteoblasts and osteoclasts,
of osteoclast activity [21]. the two of which function by cross talk and

Tooth Movement 3

Kantarci A, Will L, Yen S (eds): Tooth Movement. Front Oral Biol. Basel, Karger, 2016, vol 18, pp 1–8
DOI: 10.1159/000351894
signaling [25]. The number of osteoblasts de- matrix proteins, whereas chloride channel
creases with age, affecting the balance of bone de- 7 maintains osteoclast neutrality by shuffling
position and resorption and potentially leading to chloride ions through the cell membrane.
osteoporosis [30]. RANKL, a key regulator of osteoclast function
Mesenchymal stem/progenitor cells have been [39, 40], is synthesized by osteoblasts and pro-
isolated from jaw bones of both humans and ro- motes osteoclast differentiation, suggesting that
dents [31–33]. Stem/progenitor cells from the jaw osteoblasts control osteoclast differentiation, but
bone were clonogenic and had potent osteogenic not function [42].
potential in vitro and in vivo [33]. Compared with
iliac crest cells, mandibular mesenchymal stem/ Matrix Proteins
progenitor cells appear to proliferate rapidly with In the alveolar bone, the most abundant extracel-
delayed senescence, express robust alkaline phos- lular matrix component is collagen type I [43]. In
phatase and accumulate more calcium in vitro addition, alveolar bone contains noncollagenous
[31]. Specifically, mesenchymal stem/progenitor proteins such as osteocalcin, osteopontin, osteo-
cells from long bones yield greater bone marrow nectin, bone sialoprotein and fibronectin as well
area than mandibular mesenchymal stem/pro- as proteoglycans including lumican, fibromodu-
genitor cells when transplanted heterotopically in lin, decorin, biglycan and versican. Osteocalcin
vivo [32]. acts as a hormone and causes pancreatic beta cells
Osteocytes are the most numerous cells in ma- to release more insulin, and at the same time di-
ture bone, and can live as long as the organism rects adipocytes to release adiponectin, which in-
itself [34]. Osteocytes are derived from functional creases sensitivity to insulin [44]. Osteopontin is
osteoblasts that are embedded in mineralized a phosphorylated, sialic acid containing glyco-
bone in the process of bone apposition. The space protein that can be extracted from the mineral-
that an osteocyte occupies is called a lacuna. Hy- ized bone matrix. Matrix metalloproteinase-1,
droxyapatite, calcium carbonate and calcium metalloproteinase-2 [43, 45] and cathepsin [46,
phosphate is deposited around osteocytes [35, 47] are considered to be particularly important in
36]. bone resorption. They cleave type I collagen most
Whereas osteoblasts (and osteocytes) derive efficiently within the triple-helical body of the na-
from the mesenchymal/mesodermal lineage, os- tive conformation and is active at neutral pH,
teoclasts originate from an entirely different whereas cathepsin K degrades type I collagen in a
source: the hematopoietic/monocyte lineage [37, similar manner but is active at low pH in the acid-
38]. Osteoclasts are formed by the fusion of mul- ic microenvironment beneath the ruffled border
tiple monocytes, and, therefore, multinucleated of osteoclasts [48].
[39, 40]. Their unique properties include adher-
ence to endosteal bone surfaces, and secret acid
and lytic enzymes that destroy mineral and pro- Periodontal Ligament and Alveolar Bone
tein structures. An array of transcription factors Resorption and Remodeling
controls osteoclast differentiation [40]. Osteo-
clasts are characterized by robust expression of Can one type of force with a specific magnitude
tartrate resistant acid phosphatase, specified os- and frequency preferably activate osteoblasts,
teoprotegerin, cathepsin K, and chloride channel whereas another force type preferably activates
7 (ClCN7) [41]. Osteoprotegerin blocks nuclear osteoclasts [49]. One can only begin to address a
factor-kappa B (RANK) and RANK ligand question such as this by understanding how
(RANKL) docking; cathepsin K destroys bone stem/ progenitor cells in the PDL and alveolar

4 Jiang · Guo · Chen · Zheng · Zhou · Kim · Embree · Songhee Song · Marao · Mao

Kantarci A, Will L, Yen S (eds): Tooth Movement. Front Oral Biol. Basel, Karger, 2016, vol 18, pp 1–8
DOI: 10.1159/000351894
differentiate into mature cells, including fibro- tion that no longer has normal tissue architecture.
blasts, osteoblasts, osteoclasts and endothelial Macrophages are responsible for removing the
cells. Two interrelated processes in orthodontic hyalinized tissues prior to which little tooth
tooth movement are deflection (bending) of the movement occurs [55]. Extracellular matrix and
alveolar bone and remodeling of the periodonti- cell distortion causes structural and functional
um: the periodontal ligament, alveolar bone and changes in cell membrane, and cytoskeletal pro-
cementum [50]. In the ‘pressure-tension theory’, teins. At the same time, numerous submembrane
the PDL senses a change in mechanical forces or proteins associate in cellular focal adhesions.
stresses. The theory proposes that PDL progeni- These complex structural or functional adapta-
tor cells differentiate into compression-associat- tions will transmit signals to the cytoplasm and
ed osteoclasts and tension-associated osteoblasts, mediate cell adhesion by integrin activation [56].
causing bone resorption and apposition, respec- Alveolar bone resorption occurs on the com-
tively [51]. The following biological processes are pression side during tooth movement. Bone re-
proposed on the compression side: disturbance of sorption occurs through osteoclastic activity, thus
blood flow in the compressed PDL, cell death in creating irregular cavities in bone that later will be
the compressed area of the PDL (hyalinization), filled by newly formed bone owing to osteoblast
resorption of the hyalinized tissue by macro- activity. Two processes involved in bone resorp-
phages, and undermining bone resorption by os- tion are the dissolution of minerals and the deg-
teoclasts beside the hyalinized tissue. It is pro- radation of the organ matrix, which consists of
posed that tooth movement follows the comple- type I collagen. These processes are driven by en-
tion of these processes on the compression side, zymes, including matrix metalloproteinase and
but not before. lysosome cysteine proteinases [48]. Orthodontic
On the tension side, it is proposed that the forces result in the deformation of blood vessels
periodontium, including the PDL, alveolar bone and disarrangement of surrounding tissues. Sub-
and cementum remodels and undergoes bone ap- sequently, blood flow and periodontal tissue
position. Osteoblasts differentiate from mesen- adapt to the compression force, or when they fail,
chymal stem/progenitor cells. Mature osteoblasts are responsible for cell death and tissue necrosis
form the osteoid or type I collagen matrix, which [57].
is followed by mineralization [52]. Endothelial The rate of orthodontic tooth movement is
nitric oxide synthase mediates bone formation on affected by multiple factors such as the magni-
the tension side of orthodontic forces [53]. tude, frequency, and duration of mechanical
Force magnitude has been associated with bio- forces that are applied to the teeth or bone. Me-
logical events, although most of these associa- chanical forces change vascularity and blood
tions are conjectures. ‘Direct resorption’ is associ- flow, resulting in the synthesis and release of
ated with light force application, tissue and cell molecules such as neurotransmitters, cytokines,
preservation, and vascular potency. ‘Indirect re- growth factors, colony-stimulating factors that
sorption’ and hyalinization are associated with regulate leucocyte, macrophage, and monocyte
heavy forces that cause crushing injury to PDL lines [58, 59].
tissues, cell death, hemostasis, and cell-free PDL Protein phosphorylation mediated by protein
and adjacent alveolar bone zones [54]. Mechani- kinase enzymes is critical to the understanding of
cal forces often cause hyalinization leading to ne- orthodontic tooth movement [56, 60, 61]. Cyto-
crosis in the PDL and lead to delayed bone re- plasmic signaling proteins Hh, sonic hedge-hog,
sorption. Hyalinization occurs in the PDL and is the transforming growth factor-β superfamily,
proposed to indicate hyaline-like tissue forma- and many transcriptional factors and ions

Tooth Movement 5

Kantarci A, Will L, Yen S (eds): Tooth Movement. Front Oral Biol. Basel, Karger, 2016, vol 18, pp 1–8
DOI: 10.1159/000351894
(Ca2+, PO3–) enhance or suppress gene expres- ing mechanical stresses to biochemical events
sion. Matrix metalloproteinases (MMP) is an in- with a net result of bone apposition and/or bone
dispensable enzyme in bone remodeling. MMP-2 resorption. Despite our improved understanding
protein is induced by compression and increases of mechanical and biochemical signaling mecha-
significantly in a time-dependent fashion, reach- nisms, how mechanical stresses regulate the dif-
ing a peak after 8 h of force application. On the ferentiation of stem/progenitor cells into osteo-
tension side, MMP-2 significantly increases after blast lineage and osteoclast lineage is largely un-
one hour of force application but gradually re- known. An improved understanding of osteoblast
turns to baseline within eight hours [62]. The differentiation from mesenchymal stem/progeni-
cleavages of procollagen yields procollagen type I tor cells and osteoclastogenesis from the hemato-
C-terminal propeptide and procollagen type I N- poietic/monocyte lineage is essential to advance
terminal propeptide that may serve as bone for- orthodontics. Design of orthodontic force sys-
mation markers [63]. Normal chloride channels tems has been largely empirical since the Angle
play a key role in osteoclastic alveolar bone re- era. The orthodontics community is now
sorption in orthodontic tooth movement [40]. equipped with tools to begin advancing the un-
Cystic fibrosis, a pathological bone condition is derstanding of orthodontic tooth movement via
characterized by mutated cellular chloride chan- cellular and molecular events, including how
nels encoded by polymorphic nucleotide se- stem cells differentiate into osteoblasts and osteo-
quences in the ClCN7 gene [50]. clasts.

Acknowledgements
Conclusion
The authors wish to thank F. Guo, H. Keyes and J. Me-
The periodontal ligament and alveolar bone make lendez for technical and administrative assistance. The
up a functional unit and undergo robust remodel- effort for composition of this article is supported by
ing in orthodontic tooth movement. Complex NIH grants R01DE018248, R01EB009663, and
molecular signaling is responsible for transduc- RC2DE020767 to J.J. Mao.

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Jeremy J. Mao, DDS, PhD

Center for Craniofacial Regeneration, Columbia University Medical Center
630 W. 168 St. – PH7E – CDM
New York, NY 10032 (USA)
E-Mail [email protected]

8 Jiang · Guo · Chen · Zheng · Zhou · Kim · Embree · Songhee Song · Marao · Mao

Kantarci A, Will L, Yen S (eds): Tooth Movement. Front Oral Biol. Basel, Karger, 2016, vol 18, pp 1–8
DOI: 10.1159/000351894
Section 1: Biology and Metabolism of Alveolar Bone
Kantarci A, Will L, Yen S (eds): Tooth Movement. Front Oral Biol. Basel, Karger, 2016, vol 18, pp 9–16
DOI: 10.1159/000351895

Cellular and Molecular Aspects of Bone

Remodeling
Wenmei Xiao a, d · Yu Wang c, d · Sandra Pacios d, e · Shuai Li b, d · Dana T. Graves d
Departments of a Periodontology and b Implantology, School and Hospital of Stomatology, Peking University, Beijing, and
c Department of Dental Implantology, School and Hospital of Stomatology, Jilin University, Jilin, China; d Department of

Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pa., USA; e Department of Periodontology,
School of Dental Medicine, Universitat Internacional de 29 Catalunya, Sant Cugat del Vallès, Spain

Abstract Cell Types Involved in Bone Remodeling

Bone remodeling is a highly coordinated process re-
sponsible for bone resorption and formation. It is initi- Bone remodeling is a lifelong process where old
ated and modulated by a number of factors including bone is removed (resorption) and new bone is
inflammation, changes in hormonal levels and lack of created (formation) [1, 2]. This process is regu-
mechanical stimulation. Bone remodeling involves the lated by different cell types that form bone (osteo-
removal of mineralized bone by osteoclasts followed by blasts), regulate bone homeostasis (osteocytes),
the formation of bone matrix through osteoblasts that resorb bone (osteoclasts) and affect bone resorp-
subsequently becomes mineralized. In addition to the tion and formation (innate and adaptive immune
traditional bone cells (osteoclasts, osteoblasts and os- cells). There are several pathologic processes that
teocytes) that are necessary for bone remodeling, sev- can affect bone remodeling whereby both bone
eral immune cells such as polymorphonuclear neutro- resorption and formation are affected and have
phils, B cells and T cells have also been implicated in been demonstrated in post-menopausal osteopo-
bone remodelling. Through the receptor activator of nu- rosis, arthritis, periodontal disease and micro-
clear factor-κB/receptor activator of the NF-κB ligand/ gravity or disuse [2].
osteoprotegerin system the process of bone resorption Osteoclasts are terminally differentiated my-
is initiated and subsequent formation is tightly coupled. eloid cells that are uniquely adapted to remove
Mediators such as prostaglandins, interleukins, chemo- mineralized bone matrix [1]. They are found in
kines, leukotrienes, growth factors, wnt signalling and pits within the bone surface which are called
bone morphogenetic proteins are involved in the regu- resorption bays, also known as Howship’s Lacu-
lation of bone remodeling. We discuss here cells and me- nae. Osteoclasts resorb bone by producing
diators involved in the cellular and molecular macha- acid that dissolves the mineral content and en-
nisms of bone resorption and bone formation. zymes that remove the organic matrix. Mature
© 2016 S. Karger AG, Basel osteoclasts anchor to the bone through RGD-
binding sites to create a sealed microenviron- vascularization phenotype called M1 or M2. M1
ment. macrophages produce cytokines such as IL-1β,
Osteoblasts are bone-forming cells that arise TNF-α and RANKL, whereas M2 monocytes/
from osteoprogenitor cells. RUNX2 (runt-related macrophages produce anti-inflammatory media-
transcription factor 2) and other transcription tors such as IL-10 and IL-4 [5]. Dendritic im-
factors control the differentiation of osteoblasts mune cells have their origin in bone marrow and
[2–4]. During bone formation, a subpopulation are found in a number of different tissues. One of
of osteoblasts undergoes terminal differentiation the first contacts between oral bacteria and the
and becomes engulfed by osteoid, at which time immune system occurs with Langerhans cells, a
they are referred to as osteoid osteocytes. Osteo- subset of dendritic cells found in mucosal surfac-
cytes which reside in lacunae are the most numer- es and skin. They function in activating the im-
ous cell type found in mature bone and are long- mune response as antigen presenting cells and
lived. They have dendritic processes that interact regulate homeostasis by modulating the response
with other osteocytes and bone-lining cells on the to oral bacteria and self-antigens. Once they de-
bone surface. Osteocytes respond to mechanical tect antigen dendritic cells travel to lymph nodes
load. Under resting conditions osteocytes express and present antigen to activate lymphocytes.
sclerostin, which directly prevents Wnt signaling The predominant cells of the adaptive immune
(described in more detail below). Sclerostin ex- response are B and T lymphocytes. Activated T
pression can be inhibited by parathyroid hor- and B cells can express RANKL and various other
mone signaling to remove this inhibitor of Wnt cytokines that typically promote osteoclastogen-
signaling and allow Wnt directed bone formation esis. B cells express TNF-α, IL-6, and RANKL to
to occur. Under basal conditions, osteocytes se- promote osteoclastogenesis. T cells can develop
crete transforming growth factor β (TGF-β), into T-helper cells, Th1, Th2 and Th17 that mod-
which inhibits osteoclastogenesis. However, ulate bone resorption. Th1-type produce IL-1 and
upon stimulation osteoblasts and osteocytes pro- TNF-α that can promote bone resorption. Th17
duce osteoclastogenic factors such as macrophage cells have recently been identified as an effector T
colony-stimulating factor-1 (CSF-1) and receptor helper cell subset characterized by the production
activator of the NF-κB ligand (RANKL) to induce of proinflammatory cytokines. IL-1 and IL-17 me-
bone remodeling [1–4]. diate osteoclast formation through induction of
Innate immune cells (primarily polymorpho- RANKL [6]. Lymphocyte subsets (Th2) produce
nuclear neutrophils (PMNS), monocytes/macro- cytokines that are anti-inflammatory, IL-4 and IL-
phages and dendritic cells) and adaptive immune 10. These cytokines reduce osteoclastogenesis and
cells (primarily lymphocytes) modulate bone re- the severity of bone loss [7].
sorption particularly under inflammatory condi-
tions. PMNs are granular leukocytes that pre-
dominate in the initial acute inflammatory re- Mediators Involved in Bone Resorption
sponse. Like other leukocytes, they are recruited
from the peripheral vasculature by chemotactic Mediators play an important role in the patho-
factors, particularly chemokines. They express a genesis of bone damage. Cytokines stimulate the
number of inflammatory cytokines (e.g. IL-1β, recruitment, formation and activity of the bone-
TNF-α, IL-6) as well as membrane-bound RANKL resorbing cell, the osteoclast. They trigger the
[4]. Macrophages are produced from the differ- chemotaxis of osteoclast precursors, the induc-
entiation of monocytes in tissue. Monocytes/ tion of genes that lead to fusion of these precur-
macrophages can have an inflammatory or a pro- sors, the maturation of osteoclasts and the

10 Xiao · Wang · Pacios · Li · Graves

Kantarci A, Will L, Yen S (eds): Tooth Movement. Front Oral Biol. Basel, Karger, 2016, vol 18, pp 9–16
DOI: 10.1159/000351895