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Current concepts in the biology of orthodontic

tooth movement
Richard S. Masellaa and Malcolm Meisterb
Fort Lauderdale, Fla

Adaptive biochemical response to applied orthodontic force is a highly sophisticated process. Many layers
of networked reactions occur in and around periodontal ligament and alveolar bone cells that change
mechanical force into molecular events (signal transduction) and orthodontic tooth movement (OTM).
Osteoblasts and osteoclasts are sensitive environment-to-genome-to-environment communicators, capable
of restoring system homeostasis disturbed by orthodontic mechanics. Five micro-environments are altered
by orthodontic force: extracellular matrix, cell membrane, cytoskeleton, nuclear protein matrix, and genome.
Gene activation (or suppression) is the point at which input becomes output, and further changes occur in
all 5 environments. Hundreds of genes and thousands of proteins participate in OTM. Gene-directed protein
synthesis, modification, and integration form the essence of all life processes, including OTM. Bone
adaptation to orthodontic force depends on normal osteoblast and osteoclast genes that correctly express
needed proteins at the right times and places. Cell membrane receptor-ligand docking is an important
initiator of signal transduction and a discovery target for new bone-enhancing drugs. Despite progress in
identification of regulatory molecules, the genetic mechanism of “orchestrated synthesis” between different
cells, tissues, and systems remains largely unknown. Interpatient variation in mechanobiological response is
most likely due to differences in periodontal ligament and bone cell populations, genomes, and protein
expression patterns. Discovery of mutations in OTM-associated genes of orthodontic patients, including
those regulating osteoclast bone-matrix acidification, chloride channel function, and osteoblast-derived
mineral and protein matrices, will permit gene therapy to restore normal matrix and protein synthesis and
function. Achieving selectivity in targeting abnormal genes, cells, and tissues is a major obstacle to safe and
effective clinical application of gene engineering and stem-cell mediated tissue growth. Orthodontic
treatment is likely to evolve into a combination of mechanics and molecular-genetic-cellular interventions: a
change from shotgun to tightly focused communication with OTM cells. (Am J Orthod Dentofacial Orthop

ife’s complexity and organization are illustrated bers determine the molecular genetic responses making
in the biological phenomena underlying orth- tooth movement possible. In the dramatic words of
odontic tooth movement (OTM). A daunting Kiberstis et al,1 “the robust and unceasing activities of
array of coordinated biochemical reactions occur in and osteoblasts and osteoclasts imbue humans with the
around cells, leading to end points of protein synthesis, mechanical prowess to climb mountains or run mara-
mitosis (cell division), and cell differentiation. Mechan- thons” and, we add, to undergo orthodontic treatment.
ically induced, cell-mediated time and space changes in
bone and soft tissue return the craniomandibular system
to homeostasis. PURPOSE
Capability of adaptive response to applied orth- This article reviews and synthesizes current bio-
odontic force rests in the DNA of periodontal ligament medical literature on processes in OTM. It seeks to link
(PDL) and alveolar bone cells. Cell vitality and num- clinical orthodontics with mainstream molecular-ge-
netic research. It does not propose a complete picture
From the Department of Orthodontics, College of Dental Medicine, Nova but orients the reader to bases for the bioadaptability of
Southeastern University, Fort Lauderdale, Fla.
Associate professor. orthodontic force application and areas where progress
Professor and chair. in mechanobiological diagnosis and treatment is likely.
Reprint requests to: Richard S. Masella, Department of Orthodontics, College
of Dental Medicine, Nova Southeastern University, 3200 S University Dr, Fort
The demands of professionalism require orthodon-
Lauderdale, FL 33328; e-mail, rmasella@nsu.nova.edu. tists to be conversant with biological principles under-
Submitted, April 2005; revised and accepted, July 2005. lying treatment. Numerous instances link such knowl-
Copyright © 2006 by the American Association of Orthodontists. edge to better patient care.2,3 Roberts and Hartsfield4
doi:10.1016/j.ajodo.2005.12.013 even suggested that the importance of bone pathophys-
American Journal of Orthodontics and Dentofacial Orthopedics Masella and Meister 459
Volume 129, Number 4

iology in treatment outcomes requires orthodontists to 3-base codes for long, ordered amino acid chains
be craniofacial bone specialists. (polypeptides or proteins). Genes are made of coding
If orthodontists and other dental specialists neglect sequences, “exons,” separated by noncoding sequences,
the biology of craniofacial bone and attendant thera- or “introns.” Knowing the functional significance of
peutic implications, they risk a status closer to techni- 20,000 to 25,000 human genes and regulatory DNA in
cians than to front-rank health professionals. 23 chromosome pairs, and the possible 100,000⫹
Discoveries in the molecular biology and genetics proteins they encode will no doubt provide accurate
of bone and connective tissue physiology permit appre- definitions of health and disease, and open roads to
ciation of the complexity and regulatory sophistication improved orthodontic treatment.9,11
of OTM.4,5 Yet aspects of biomedical science can The challenge in researching the human genome’s 6
intimidate clinicians. Knowledge of organic chemistry, billion complementary base pairs is overwhelming.
biochemistry, and physiology from predental and den- Watson et al12 reminded us that the DNA alphabet is
tal education helps orthodontists understand the behav- limited to 4 letters: A, T, C, and G, denoting nucleotide
ior of OTM components. Basic chemistry includes bases adenine, thymine, cytosine, and guanine. In
molecular-ionic covalent (electron) bonding, the rela- double-stranded DNA, adenine from 1 strand typically
tionship between molecular structural change and func- pairs with thymine from the other; likewise, cytosine
tional change, and the readiness of cell surface and pairs with guanine, a bonding pattern called base
intracellular (cytoskeletal) proteins to communicate complementarity. If a single letter represents each
with the extracellular matrix (ECM) through receptor- nucleotide base, the human genome would make a
ligand (binding protein) docking and signaling protein million pages of text. A mere 1.1% to 1.5%, or 11,000
diffusion or active transport. to 15,000 pages, are represented by genes.11
Adding complexity is the genome’s lifetime ten-
GENOMIC REGULATION dency for base sequences to change (mutate) in re-
A healthy skeleton is a feedback-controlled system sponse to genetic-environmental input, defects in
that “continuously integrates signals and responses chromosome replication, and unknown reasons. For ex-
which sustain its functions of delivering [systemic] ample, cystic fibrosis is characterized by defective cellular
calcium while maintaining strength.”6 Abundant scien- chloride channels, made of mutant proteins encoded by
tific literature on control of gene expression proves that polymorphic (differently arranged) nucleotide sequences
this is the era of genomic regulation.6,7 Three years in the ClCN7 gene.11 Normal chloride channels play a key
after the discovery of the human genome structure, the role in osteoclastic bone resorption in OTM.13,14 A
search is on for controllers of gene expression and thousand polymorphisms discovered in the chloride
coordination, including those of the skeleton.8 These channel gene can cause cystic fibrosis. How many total
are critical issues in adaptive responses provoked by polymorphisms exist in this and hundreds of other
orthodontic forces. genes expressed in OTM, and what are their clinical
Michael Eisen of the Lawrence Berkeley National implications for osteoclastic bone resorption and all
Laboratory stated that “buried in the DNA sequence is metabolic processes of tooth movement?
a regulatory code akin to the genetic code but infinitely
more complicated.”8 Hood et al9 add that “gene regu- SYSTEMS ANALYSIS
latory networks integrate dynamically changing inputs The challenge in OTM is understanding systems
from signal transduction pathways and provide dynam- rather than components.9 System comprehension, how-
ically changing outputs to the batteries of genes medi- ever, is easier said than done. Although we can see the
ating physiological and developmental responses,” in- entire system, “the information contained in . . . thou-
cluding OTM. sands of data points is beyond our ability to interpret
DNA, GENES, BASE PAIRING The first step in understanding OTM systems is the
The DNA in PDL and alveolar bone cell chromo- collection of a comprehensive expressed messenger
somes holds the keys to life and OTM. DNA is divided ribonucleic acid (mRNA: DNA gene sequences con-
into 3 parts: sugar and phosphate “backbone” mole- verted to complementary RNA sequences) transcript
cules, and nitrogen-containing cyclic bases.10,11 The database for osteoblasts, osteoclasts, osteocytes, fibro-
combination makes an extremely reactive molecule. blasts, mesenchymal stem cells (MSCs), cementoblasts,
Regulatory regions of nucleotide (DNA building block) cementoclasts, and macrophages. Present technology
sequences are scattered within long DNA molecules. A allows detection of single mRNA transcripts per cell.9
“gene” is a specific base sequence containing mamy Knowing all mRNA transcripts of pertinent cells means
460 Masella and Meister American Journal of Orthodontics and Dentofacial Orthopedics
April 2006

knowing all proteins that the system can synthesize. Molecular genetics of osteoblast differentiation
Protein function is inferred by comparisons with exist- and function
ing proteomics databases or via experimentation. Although many genes control the complex process
For example, osteoblasts and fibroblasts are almost of osteogenesis, the TF Cbfa1 is the earliest expressed
genetically identical. All genes expressed in fibroblasts and most specific marker of bone formation.16 Other
are expressed in osteoblasts.16 Only 2 osteoblast-spe- bone-forming genes encode proteins for GFs, bone
cific mRNA transcripts are known: one for the tran- morphogenetic proteins (BMPs), transforming growth
scription factor (TF, a protein enhancing or suppressing
factor-beta (TGF-␤), and GF-associated internal signal-
gene expression) Cbfa1, the other for the TF osteocal-
ing molecules.21-23Importantly, osteoblast differentia-
cin, an inhibitor of osteoblast function. Thus, present
tion and proliferation are separate processes controlled
knowledge is that osteoblasts can synthesize only 2 base
by different genes.24
proteins that fibroblasts cannot.16
Expanding the pressure-tension theory, multi-po-
Currently, 96 genes are identified in human osteo-
tential MSCs begin differentiating within hours of
genesis.17 Functionally, 44 are grouped as growth
orthodontic force application as specialized molecules
factors (GFs), 30 as ECM proteins, and 8 as cell
are synthesized in the PDL and alveolar bone.25,26
adhesion molecules. Simultaneous gene expression is
Local osteoblasts and osteocytes express early-response
studied in commercially available microarrays that
connective-tissue GF, whereas osteoclasts and osteo-
permit complementary binding and analysis of experi-
cytes produce the ECM protein osteopontin.27 Connec-
mental DNA samples with known DNA sequences.
tive-tissue GF promotes osteoblast precursor prolifera-
Despite advances, development of a complete OTM
“parts list” with “parts function” is many years tion, mineralization of new bone by mature osteoblasts,
away.7,18 Linear depictions of signaling pathways fail and vasculogenesis.1,27,28
to portray 3-dimensional complexity. Even molecular A “paravascular osteogenic response” is noted in
pathways and networks with relatively few components widened (tensional) zones of the PDL and expanded
“are configured into systems that display complex midpalatal and facial sutures.27 Osteoblast differentia-
behaviors.”5,18 A complete parts catalogue would in- tion is a 5-generation process starting with stem-cell
clude protein-coding and nonprotein-coding genes, migration from blood vessel walls, or MSC precursor
TFs, and mediators of cell-cycle progression and chro- activation, and preosteoblast formation at about 10
mosome structure and function. It will also include hours postforce. TF genes Cbfa1 (also called Runx-2)
many undiscovered functional human DNA sequences. and Osterix help control this process (Fig 1).29,30
The magnitude of challenge in delineating genomes (Cbfa1 is also expressed in the osteoblast-homologous,
and proteomes is shown in the 20-million-strong dentin-synthesizing odontoblast.16,31) The late-acting
mRNA database generated for normal prostate tissue TF-coding osteocalcin gene also controls osteoblast
and 1 prostate-cancer cell line. Some 300 prostate- differentiation through an inhibitory effect.32 Other TFs
specific genes were identified, along with 554 ex- exerting positive or negative control over osteoblast
pressed TFs.9 differentiation and proliferation will be discovered.
All major GF families help control osteoblast dif-
PRESSURE-TENSION PERSPECTIVE ferentiation during embryonic development, including
Most orthodontists became aware of the role of TGF-␤, fibroblast GF-1, and Indian hedgehog.16,28,32
cells in OTM in the “pressure-tension theory,” linking Bone formation begins 40 to 48 hours postforce.27
“physiologic” force application with PDL compres- Regulatory sequences of most genes involved in secret-
sional and tensional changes and subsequent activation ing bone ECM contain 5 to 10-base Cbfa1 binding
of MSCs. The theory proposes that force-subjected sites, which help control bone matrix secretion by
PDL progenitor cells differentiate into compression- mature osteoblasts.16 The pressure-tension perspective
associated osteoclasts and tension-associated osteo- is enlarged in noting that “bone resorption and deposi-
blasts, causing bone resorption and apposition, respec- tion can be present in any tension site, as well as any
tively.19 “Direct resorption” is associated with light compression site.”27,33,34
force application (⫾ 50-100 g per tooth), tissue and cell Other genes participate in mechanically induced
preservation, and vascular patency.20 “Indirect (under- bone modeling, expressing proteins for enzymes nitric
mining) resorption” and hyalinization are associated with oxide synthetase, prostaglandin G/H synthetase, and
bio-intolerant heavy or necrotizing forces causing crush- glutamate/aspartate transporter. Parathyroid hormone
ing injury to PDL tissues, cell death, hemostasis, and helps induce expression of insulin-like GF and estrogen
cell-free PDL and adjacent alveolar bone zones.19,20 receptor-beta.27 The recently discovered low-density
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Fig 1. Transcriptional control of osteoblastic differentiation and progeny of pleuripotent MSCs.

Preosteoblasts are derived from 2 sources: MSC and pericytes from blood-vessel walls. TF Cbfa1
is early promoter of osteoblast differentiation. Osterix is late-differentiation TF that induces mature
osteoblasts capable of expressing osteocalcin, a TF-inhibiting osteoblast differentiation. BSP, bone
sialoprotein; Col-1, type 1 collagen; OC, osteocalcin; Osx, osterix; Msx2, homeobox gene.

lipoprotein receptor-related protein 5 (LRP5) gene con- Osteoblast receptor-ligand docking not only changes
trols bone formation through modifying osteoblast cell form and function and initiates signaling, but also
proliferation and increasing bone mass.6,26 LRP5 mu- serves as a potential point of therapeutic modification.
tation in both alleles (gene forms) causes loss of Drugs that enhance or block activity of osteoblast
osteoblast function and osteoporosis-pseudoglioma receptors are under investigation.
syndrome, characterized by very low bone mass.6,24 Finally, a family of molecules known as “ho-
Single-gene mutations in LRP5 might cause gain of meobox” proteins (specialized DNA sequences in ex-
function resulting in osteoblast hyperactivity and in- ons of many regulatory genes) also help control osteo-
creased bone mass. LRP5 might mediate other molec- blast differentiation. Msx1 protein is a key modulator
ular genetic processes, including cancer.6 of bone development and modeling, participating in
Mutations in any OTM-associated gene induce embryologic body patterning and skeletal adaptation in
mutant, missing, insufficient, or excess proteins and, adulthood.16 Msx2 could be another regulator of Cbfa1
without genetic redundancy, will alter clinical response. expression. The homeobox protein Hoxa-2 controls
The more extensive the single gene mutation or number second branchial arch patterning and might suppress
of mutant genes, the greater the clinical deficit. both Cbfa1 expression and bone formation.
Osteoblasts contain a rich array of functional cell
surface receptors open to protein docking. BMPs bind
to such receptors, triggering a signaling pathway that NEUROTRANSMITTERS
promotes osteoprogenitor cell differentiation and up- Somatosensory neurons transmit signals from pe-
regulation (increase) of osteoblast function.35-37 BMPs ripheral tissues to the central nervous system (CNS).
can induce Cbfa1 expression. In turn, BMP expression An example of component multi-functionality is the
and signaling might be controlled by signaling mole- discovery of the efferent (output) function of afferent
cules and Hh genes and proteins.32,36,38 Growth hor- (input) neurons: release of biologically active proteins
mone promotes bone formation through ligation with that contribute to neurogenic inflammation. Increased
GF receptors on osteoblast surfaces and stimulation of concentration of these PDL neuropeptides during OTM
insulin-like GF-1.39 indicates their importance.40,41
462 Masella and Meister American Journal of Orthodontics and Dentofacial Orthopedics
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With application of physiologic orthodontic force, ing, cathepsin K destroys bone matrix proteins, whereas
PDL peripheral nerve fibers release calcitonin gene- chloride channel 7 maintains osteoclast neutrality by
related peptide (CGRP) and substance P.40,41 Other shuffling chloride ions through the cell membrane.
undiscovered neurotransmitters might mediate the in- These molecules are also targets of drug discovery.
flammatory process. Besides acting as neurotransmit- A patient’s bone resorption potential and timely
ters, CGRP and substance P serve as vasodilators, OTM outcome then depend on recruitment of mature
inducers of increased vascular flow and permeability osteoclasts and precursors, osteoclast differentiation,
(diapedesis), and stimulators of plasma extravasation and numbers of functional osteoclasts at the bone-PDL
and leukocyte migration into tissues (transmigration). interface. Clinical success also hinges on normal oste-
A work-horse molecule, CGRP, induces bone forma- oclast and osteoblast genes that correctly express
tion through osteoblast proliferation and osteoclast needed proteins in adequate amounts at the right times
inhibition.42-44 and places, including regulatory molecules such as
Receptors for CGRP are found on osteoblasts, tumor necrosis factor and its receptor, colony stimulat-
monocytes, lymphocytes, and mast cells. Receptor ing factor-1, OPG, and RANK and RANKL.27
activation (docking) results in amplified 2-way inter- The earliest marker of bone resorption could be the
cellular communication, promoting cytokine (inflam- cytokine interleukin-1beta (IL-1␤). A mutant gene of
matory mediator molecule) synthesis and release.41,42 IL-1␤ might be associated with down-regulation of this
Cytokine receptors on neuropeptide molecules facili- important cytokine.27 Osteoclastic bone resorption is
tate cellular cross-talk and synthesis of other molecules also facilitated by PGE2, nitric oxide, IL-6, and other
that change cell behavior. Signaling pathways change inflammatory cytokines.48
mechanical force into molecular events (signal trans- RANK and RANKL are key proteins regulating
duction) and tooth movement.45 At least 10 networked osteoclast function.13,14,24,27 Synthesis of RANKL by
signal transduction pathways participate in OTM. Dam- osteoblasts and its lifetime role in promoting osteoclast
age to any signaling pathway can cause dysfunction and differentiation supports the idea that osteoblasts control
disease. only osteoclast differentiation, not function.24 How-
Normal PDL and alveolar bone innervation is ever, an osteoclast-originating messenger molecule was
essential to OTM-associated periodontal remodeling. recently discovered that appears to “talk” with osteo-
Healthy innervation promotes maximum blood flow blasts. This underscores the biologic concept of contin-
during OTM, whereas denervation reduces blood flow ual, 2-way cell-to-cell communication.2
and bone formation.46,47 Bone resorption is a much faster process than bone
Systemic factors such as age, nutritional status, apposition; it can take 3 months to replace bone
drug history, and metabolic bone diseases might alter resorbed in only 2 to 3 weeks.27 The molecular genetics
key molecules that mediate mechanically induced lo- of osteoclast differentiation and function might be
calized inflammation, bone modeling, and homeostatic simpler than that of osteoblasts.
bone remodeling.27
Endocrine regulation of bone physiology
Osteoclast differentiation and function Sex steroids also influence bone homeostasis (Fig 3).
Osteoclasts are specialized multinucleated giant cells Estrogen suppresses bone resorption by reducing oste-
that develop from monocyte-hematopoietic cells.13,14 oclast numbers.6 Testosterone reduces bone resorption
Their unique properties include adherence to bone in males, promotes bone formation in males and fe-
matrix and secretion of acid and lytic enzymes that males, and can be converted to estrogen to inhibit bone
destroy mineral and protein structures.13 At least 24 resorption. Much remains to be learned about estrogen-
genes and 60 proteins are implicated in positive and mediated bone resorption.24
negative regulation of osteoclastogenesis and osteoclast A central nervous system component is another
function. A series of TFs controls osteoclast differen- regulator of osteoblast function. The hormone leptin is
tiation.14,26 synthesized by fat cells and acts by binding to signal-
Roberts et al27 considered bone resorption at the transduction receptors on hypothalamic neurons.16
PDL surface the rate-limiting step in OTM. Harada and Through “hypothalamic relay,” leptin strongly inhibits
Rodan6 specified osteoprotegerin (OPG), cathepsin K, bone formation by suppressing osteoblast function
and chloride channel 7 (ClCN7) as rate-limiting agents (neuroendocrine control).24 Peripheral signaling is me-
for osteoclast differentiation and function (Fig 2). OPG diated by the sympathetic nervous system. When leptin is
blocks the TF receptor activator of nuclear factor absent because of adipocyte depletion, as in generalized
kappa B (RANK) and RANK ligand (RANKL) dock- lipodystrophy, accelerated bone growth and osteosclerosis
American Journal of Orthodontics and Dentofacial Orthopedics Masella and Meister 463
Volume 129, Number 4

Fig 2. Determinants of skeletal homeostasis and bone changes in OTM. BMP, bone morphogenetic
protein; Cbfa1, transcription factor, earliest marker of osteogenesis; CGRP, calcitonin gene-related
peptide; ClCN7, chloride channel 7; CSF-1, colony stimulating factor 1; CTGF, connective tissue
growth factor; ER-␤, estrogen receptor-beta; GH, growth hormone; GLAST, glutamate/aspartate
transporter; Hoxa-2, homeobox gene; IGF, insulin-like growth factor; IL-1␤, Il-6, Il-11, interleukins;
Leptin, central nervous system hormone; LRP5, low-density lipoprotein receptor-related protein 5;
Msx-2, homeobox gene; NOS, nitric oxide synthetase; OPG, osteoprotegerin; Osteocalcin, tran-
scription factor; Osterix, transcription factor promoting osteoblast differentiation; PGHS-2, prosta-
glandin G/H synthetase; PTH, parathyroid hormone; RANK/RANKL, receptor activator of nuclear
factor kappa-b and ligand; Smad, cytoplasmic signaling molecules; SOST, gene for sclerostin;
TGF-␤, transforming growth factor-beta family; TNF/R, tumor necrosis factor and receptor.

ensue. Similar to thyroid hormones or cortisol, leptin is transcription factor, [or] protein kinase, expresses a
thought to have many target organs and functions.16 function that assumes significance only in the context of
all the other functions and activities also being expressed
The proteome in the same cell (italics added).”15 He also references the
Cellular biochemistry is carried out by proteins. “thousands of genes that may be expressed in each cell in
Proteins commonly function in concert with other varying combinations (italics added).”15
proteins in complexes or networks.9 Liebler advised The level of molecular coordination within and
that “each protein, whether a transmembrane receptor, outside cells is believed to be ultracomplex. Posttrans-
464 Masella and Meister American Journal of Orthodontics and Dentofacial Orthopedics
April 2006

Fig 3. Hormonal control of bone formation and resorption.

lational modification (after ribosome-based synthesis) and alveolar bone ECM, cell membrane, cytoskeleton,
of proteins is an important point of functional change matrix of nuclear proteins, and genome (Fig 4).
and increased protein versatility.11,15,49 Phosphate Orthodontic force causes physical distortion of
(HPO3-, phosphorylation) and methyl groups (-CH3, PDL and alveolar bone cells and the ECM, triggering
methylation), other ions, and lipids might bond to many biochemical reaction cascades that affect all 5
base proteins. Protein modification results in changed micro-entities.52 ECM and cell distortion initiate struc-
3-dimensional shape (conformation), bonding poten- tural and functional changes in extracellular, cell mem-
tial, pattern of molecular folding, and molecular func- brane, and cytoskeletal proteins. At the same time,
tion.10,11,15 Gorlin et al50 referred to “molecular parsi- numerous submembrane proteins associate in “cellular
mony” in describing the ubiquitous multi-potentiality, focal adhesions.” These complex structural/functional
or pleiotropy, of human genes and protein products. adaptations transmit survival and growth signals to the
Another rich source of human protein variability is
cytoplasm and help mediate cell adhesion via integrin
“alternative splicing” of primary mRNA. One gene can
activation.53 A regulator of integrin-mediated focal
produce mRNA transcripts that differ in structure
adhesions is the enzyme focal adhesion kinase. Illus-
(differentially cut by splicing enzymes) and therefore
trating molecular parsimony, focal adhesion kinase
coding potential.4,11,15,49,50 The fibronectin gene com-
also regulates cell growth, migration, proliferation,
monly expressed in OTM is an example. The ECM
protein fibronectin is a mediator of cell-ECM inter- and survival. Protein phosphorylation mediated by
action. Differential mRNA splicing produces many protein kinase enzymes is important in all aspects of
forms of fibronectin (isoforms), each with a specific biology.53-55
function.49,51 Subsequent changes in cytoskeletal protein struc-
ture and function, such as activin polymerization and
Intracellular and extracellular environments depolymerization, continue the signaling process, which
Orthodontic force-induced system adaptation oc- can also involve molecular-ionic diffusion outside cells,
curs in the context of 5 related microstructures: PDL attachment to migrating cells or carrier molecules,
American Journal of Orthodontics and Dentofacial Orthopedics Masella and Meister 465
Volume 129, Number 4

Fig 4. Mechanical force-induced reciprocal communication between 5 micro-environments of

OTM. By using osteoblast schematic, mechanical force causes distortion of PDL and alveolar bone
cells and triggers multilevel cascade of signal transduction pathways. Structural changes in
environmental componenets cause functional changes, including signal input. Genomic expression,
or lack therof, is turn-around point at which signal input becomes output. BSP, ECM bone
sialoprotein; Ca⫹⫹, free calcium; CM, cell membrane; CS, cytoskeleton or cytoplasmic protein
network; DC-STAMP, dendritic cell-specific transmembrane protein; ECM, PDL and alveolar bone
extracellular matrix; FAK, enzyme focal adhesion kinase; FN, ECM protein fibronectin; G, genome,
GFR, growth factor receptor; mRNA, messenger RNA; N, nuclear matrix proteins; OPN, ECM
protein osteopontin; TF, transcription factor; TNFR, tumor necrosis factor receptor; tRNA, transfer

transcytosis through cells, or released cell-membrane changes can occur throughout life. Hartl and Jones11
vesicles.38,56 emphasized that there is “a great deal to be learned
about molecular mechanisms underlying epigenetic
Signal input, genetic output modifications.”
Cytoplasmic signaling proteins Hh, sonic hedge-
hog, the TGF-␤ superfamily, and many TFs and ions PDL and alveolar bone cell death and renewal
(Ca⫹⫹, PO3-) reach the nuclear matrix and then Apoptosis is a critically important process in skel-
genome, resulting in enhanced or suppressed gene etal maturation, adult bone remodeling, and bone re-
expression. Input becomes output as gene-expressed pair.25 In health, a close linkage exists between bone
proteins, or protein synthesis inhibition, mobilize mi- cell proliferation, differentiation, and apoptosis, result-
tosis, cell motility, secretion of other proteins, and ing in an adequate pool of osteoblasts and osteoclasts
programmed cell death (apoptosis) that further modify for bone homeostasis.22,25,57
cytoskeleton, cell membrane, and ECM.52 The process In reducing osteoblast numbers through apoptosis
is continuous (Fig 4). and thereby decreasing bone formation, the SOST gene
Changes in cell environment (development, aging, is an important regulator of bone remodeling.21-25,27,29
external conditions) might also change the patterns of Located in chromosome 17q12-q21 (long arm, region
gene expression.11 Epigenetic regulation of gene ex- 1-2 below centromere to region 2-1), SOST expresses
pression involves heritable changes not from DNA base the protein sclerostin, a BMP-antagonist and signaling
sequence changes but from chemical modification of inhibitor.6,21,25,27 The Cbfa1 gene is part of the SOST
bases ATCG or TFs bound with DNA. Such genomic gene promoter.29 Therapeutic agents blocking the ac-
466 Masella and Meister American Journal of Orthodontics and Dentofacial Orthopedics
April 2006

tion of sclerostin might allow restoration of osteopo- sponse, tooth movement, and return to homeostasis.
rotic bone. PDL and alveolar bone cells are sensitive environment-
The many proteins involved in signal transduction, to-genome-to-environment communicators, and the
TF control, and cell cycle regulation are rapidly de- brain and heart of OTM.
graded after use as a means of regulating their activi- The following biological concepts are noted:
1. Gene-directed protein synthesis and modification,
Progress in diagnosis and treatment and integration of many proteins, form the essence
of all life processes, including OTM.
Interpatient variability in mechanical response is
2. PDL and alveolar bone cells provide hundreds of
common in orthodontic practice. Reasons can include
differences in PDL and alveolar bone cell numbers and genes and thousands of proteins for OTM.
genomes, including genes for signaling proteins; num- 3. Bone adaptation to orthodontic force depends on
bers of white blood cells, GFs, and cytokines per normal osteoblast and osteoclast genes that cor-
volumetric measure of tissue-blood; alveolar bone min- rectly express needed proteins in adequate
eral density; and PDL and alveolar bone vascularity per amounts at the right times and places.
volumetric tissue measure. 4. PDL and alveolar bone cells constantly “talk” via
The ENCODE (ENCyclopedia Of DNA Elements) molecular messengers or signaling. Communica-
project has started identifying “all structural and func- tion is a 2-way process.
tional elements of the human genome.”58 This and 5. Healthy and pathological bone metabolism in-
much other research will eventually permit correlation volves many interactions between genetic and
of patient genotype with clinical presentation and environmental (epigenetic) factors. This adds to
laboratory-derived protein profiles. This will allow the challenge of understanding bone pathophysi-
orthodontists to identify biological promoters and in- ology.6
hibitors of OTM and plan molecular intervention to 6. The molecular genetic processes underlying OTM
maximize adaptive response. function as a feedback system of checks and
If gene expression in tissues subjected to mechan- balances. Activator molecules beget suppressor
ical force shows patterns of alteration in secreted molecules and return to steady state.
proteins in blood or gingival crevicular fluid, perhaps 7. OTM biology can be envisioned in the physical
these media can serve as windows for diagnosis and context of PDL-alveolar bone ECM, cell mem-
prognosis, and sources of active-treatment biomarkers brane, cytoskeleton, nuclear matrix, and genome,
for assessing mechanics.48,59,60 giving a relatively broad perspective on location
On another front, embryology shows that the PDL, and flow of processes critical to adaptive response.
alveolar bone, dentin, and dental pulp are neural-crest 8. Receptor-ligand docking is a potent and common
derivatives.61 A short step is identification of undiffer- initiator of signal transduction of mechanical
entiated adult neural-crest cells from marrow spaces forces into molecular events and OTM. It is also a
and pulp as candidates for resolution of craniofacial discovery target for bone-enhancing drugs.
skeletal and dental defects. Discovery of molecular 9. Despite identification of many regulatory mole-
signals that induce stem-cell differentiation and cell- cules, the genetic mechanism of “orchestrated
delivery methods are necessary elements. A roadblock synthesis,” or how genes and molecules work in
to stem-cell enhancement, as with gene engineering, is concert through DNA “command centers” to in-
inability to selectively target deficient genes, cells, and duce and coordinate cell mobility, differentiation,
tissues. Yet, as Helms and Schneider61 state, “cellular proliferation, function, and apoptosis, “still re-
and molecular therapies, rather than [brackets, arch- main[s] largely unknown.”61
wires], handpieces and scalpels, may one day be used 10. Identification of mutations in OTM-associated
by [orthodontists and] dentists to treat [craniofacial] genes of orthodontic patients, especially those
afflictions.” driving osteoclast proton pumps (mineral matrix
acidification) and chloride channels, and osteo-
CONCLUSIONS blast-derived mineral and protein matrices, will
We communicate with PDL and alveolar bone cells permit gene therapy to restore normal matrix and
in applying orthodontic forces to teeth and bones. In protein synthesis and function. Achieving cell and
providing genomic-derived layers of networked bio- tissue selectivity in repairing mutant genes with
chemical processes to meet homeostatic-disturbing engineered DNA sequences, or in using stem cells
orthodontic mechanics, these cells enable bone re- to grow craniofacial tissues, is a major obstacle.
American Journal of Orthodontics and Dentofacial Orthopedics Masella and Meister 467
Volume 129, Number 4

These therapies are perhaps 10 to 15 years away in 20. Proffit WR, Fields HW Jr. Contemporary orthodontics. 3rd ed. St
everyday orthodontics. Louis: Mosby; 2000.
21. Winkler DG, Sutherland MK, Geoghegan JC, et al. Osteocyte
11. Interpatient variation in mechanobiological re- control of bone formation via sclerostin, a novel BMP antagonist.
sponse is most likely due to differences in bone EMBO J 2003;22:6267-76.
and PDL cell populations, genomes, and protein 22. Mackie EJ. Osteoblasts: novel roles in orchestration of skeletal
expression patterns. architecture. Int J Biochem Cell Biol 2003;35:1301-5.
12. Orthodontic treatment probably will evolve into a 23. Bu R, Borysenko CW, Li Y, et al. Expression and function of
TNF-family proteins and receptors in human osteoblasts. Bone
combination of mechanics and molecular-genetic- 2003;33:760-70.
cellular interventions: a change from shotgun to 24. Karsenty G. The complexities of skeletal biology. Nature 2003;
focused communication with OTM cells.8 423:316-8.
25. Sutherland MK, Geoghegan JC, Yu C, et al. Sclerostin promotes
We thank Drs Roberto Carvalho, Ze’ev Dav- the apoptosis of human osteoblastic cells: a novel regulation of
idovitch, J. K. Hartsfield, Jr, and W. E. Roberts for their bone formation. Bone 2004;35:828-35.
insights, inspiration, and graciousness. 26. Short F, Masella R, Meister M. The role of growth factors in
controlling osteoblast differentiation. Today’s FDA Feb 2002;
REFERENCES 27. Roberts WE, Huja S, Roberts JA. Bone modeling: biomechanics,
molecular mechanisms, and clinical perspectives. Sem Orthod
1. Kiberstis P, Smith O, Norman C. Bone health in the balance.
Science 2000;289:1497. 2004;10:123-61.
2. Davidovitch Z. Personal communication March 2, 2005. 28. Marie PJ. Fibroblast growth factor signaling controlling osteo-
3. Kyrkanides S, O’Banion MK, Subtelny JD. Nonsteroidal anti- blast differentiation. Gene 2003;316:23-32.
inflammatory drugs in orthodontic tooth movement: metallopro- 29. Sevetson B, Taylor S, Pan Y. Cbfa1/Runx2 directs specific
teinase activity and collagen synthesis by endothelial cells. Am J expression of sclerosteosis gene (SOST). J Biol Chem 2004;279:
Orthod Dentofacial Orthop 2000;118:203-9. 13849-58.
4. Roberts WE, Hartsfield JK Jr. Bone development and function: 30. Nakashima K, Zhou X, Kunkel G, Zhang Z, Deng JM, Behringer
genetic and environmental mechanisms. Sem Orthod 2004;10: R, et al. The novel zinc finger-containing transcription factor
100-22. osterix is required for osteoblast differentiation and bone forma-
5. Bowers PM, Cokus SJ, Eisenberg D, Yeates TO. Use of logic tion. Cell 2002;108:17-29.
relationships to decipher protein network organization. Science 31. Derringer KA, Kinden RW. Vascular endothelial growth factor,
2004;306:2246-9. fibroblast growth factor 2, platelet-derived growth factor and
6. Harada S, Rodan GA. Control of osteoblast function and regu- transforming growth factor beta released in human dental pulp
lation of bone mass. Nature 2003;423:349-54. following orthodontic force. Arch Oral Biol 2004;49:631-41.
7. Jasny BR, Roberts L. Solving gene expression. Science 2004; 32. Lee KS, Kim HJ, Li QL, Chi X-Z, Ueta C, Komori T, et al.
306:629. Runx2 is a common target of transforming growth factor beta-1
8. Pennisi E. Searching for the genome’s second code. Science and bone morphogenetic protein 2, and cooperation between
2004;306:632-5. Runx2 and Smad5 induces osteoblast-specific gene expression in
9. Hood L, Heath JR, Phelps ME, Lin B. Systems biology and new the pleuripotent mesenchymal precursor cell line C2C12. Mol
technologies enable predictive and preventative medicine. Sci- Cell Biol 2000;20:8783-92.
ence 2004;306:640-3. 33. King GJ, Keeling SD, Wronski TJ. Histomorphometric study of
10. Baker R, Murray R. PDQ biochemistry. Hamilton, Ontario, alveolar bone turnover in orthodontic tooth movement. Bone
British Columbia: Decker; 2001. 1991;12:401-9.
11. Hartl DL, Jones EW. Essential genetics: a genomics perspective. 34. Serra E, Perinetti G, D’Attillio M, et al. Lactate dehydrogenase
3rd ed. Sudbury, Mass: Jones and Bartlett; 2002. activity in gingival crevicular fluid during orthodontic treatment.
12. Watson JD, Tooze J, Kurtz DT. Recombinant DNA: a short Am J Orthod Dentofacial Orthop 2003;124:206-11.
course. New York: W. H. Freeman; 1983. 35. Tolar J, Teitelbaum SL, Orchard PJ. Osteopetrosis. N Engl J Med
13. Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation 2004;351:2839-48.
and activation. Nature 2003;423:337-41. 36. Miyazono K, Kusanagi K, Inoue H. Divergence and convergence
14. Teitelbaum SL. Bone resorption by osteoclasts. Science 2000; of TGF-beta/BMP signaling. J Cell Physiol 2001;187:265-76.
289:1504-8. 37. Massague J, Blain S, Lo R. TGF-beta signaling in growth
15. Liebler DC. Introduction to proteomics. Totowa, NJ: Humana control, cancer, and heritable disorders. Cell 2000;103:295-309.
Press; 2002. 38. Zhu AJ, Scott MP. Incredible journey: how do developmental
16. Ducy P, Schinke T, Karsenty G. The osteoblast: a sophisticated signals travel through tissue? Genes Dev 2004;18:2985-97.
fibroblast under central surveillance. Science 2000;289:1501-4. 39. Bryant DM, Wylie FG, Stow JL. Regulation of endocytosis,
17. Ho N, Jia L, Driscoll CC, Gutter EM, Francomano CA. A nuclear translocation and signaling of fibroblast growth factor
skeletal gene database. J Bone Min Res 2000;15:2095-122. receptor 1 by E-cadherin. Mol Biol Cell 2005;16:12-23.
18. Eungdamrong NJ, Iyengar R. Computational approaches for 40. Hall M, Masella R, Meister M. PDL neuron-associated neuro-
modeling regulatory cellular networks. Trends Cell Biol 2004; transmitters in orthodontic tooth movement: identification and
14:661-9. proposed mechanism of action. Today’s FDA Feb 2001;24-5.
19. Reitan K. Biomechanical principles and reactions. In: Graber 41. Davidovitch Z, Nicolay OF, Ngan PW, Shanfield JL. Neurotrans-
TM, Swain BF, editors. Current orthodontic concepts and tech- mitters, cytokines, and the control of alveolar bone remodeling in
niques. 3rd ed. Philadelphia: W. B. Saunders; 1985. orthodontics. Dent Clin North Am 1988;32:411-35.
468 Masella and Meister American Journal of Orthodontics and Dentofacial Orthopedics
April 2006

42. Anderson LI, Seybold VS. Calcitonin gene-related peptide reg- 52. Carvalho RS. Genomic basis of orthodontic forces: role of
ulates gene transcription in primary afferent neurons. J Neuro- osteopontin in osteoblasts [dissertation]. Boston: Harvard School
chem 2004;91:1417-29. of Dental Medicine; 1997.
43. Buffelli M, Pasino E, Cangiano A. In vivo acetylcholine receptor 53. McLean GW, Komiyama NH, Serrels B, et al. Specific deletion
expression induced by calcitonin gene-related peptide in rat of focal adhesion kinase suppresses tumor formation and blocks
soleus muscle. Neuroscience 2001;104:561-7. malignant progression. Genes Dev 2004;18:2998-3003.
44. Edvisson L, Cantera L, Jansen-Olesen I, Dickerson IM. Expres- 54. York JD, Hunter T. Unexpected mediators of protein phosphor-
sion of calcitonin gene-related peptide 1 receptor mRNA in ylation. Science 2004;306:2053-5.
human trigeminal ganglia and cerebral arteries. Neurosci Lett 55. Bettencourt-Dias M, Giet R, Sinka R, et al. Genome-wide survey
1997;229:209-11. of protein kinases required for cell cycle progression. Nature
45. Vandevska-Radinovic V. Neural modulation of inflammatory 2004;432:980-7.
reactions in dental tissues incident to orthodontic tooth move-
56. Parkin J, Cohen B. An overview of the immune system. Lancet
ment. Eur J Orthod 1999;21:231-47.
46. Vandevska-Radinovic V, Hals Kvinnsland I, Kvinnsland S.
57. Sutherland MK, Geoghegan JC, Yu C, Winkler DG, Latham JA,
Effect of inferior alveolar nerve axotomy on periodontal and
et al. Unique regulation of SOST, the sclerosteosis gene, by
pulpal blood flow subsequent to experimental tooth movement in
BMPs and steroid hormones in human osteoblasts. Bone 2004;
rats. Acta Odont Scand 1998;56:57-64.
47. Duan U, Inoue H, Kawakami M, Kato J, Sakuda M, et al.
Changes in bone formation during experimental tooth movement 58. The ENCODE Project Consortium. The ENCODE (ENCyclope-
after denervation of the rabbit inferior alveolar nerve. J Osaka dia Of DNA Elements) Project. Science 2004;306:636-9.
Univ Dental School 1993;33:45-50. 59. Lowney JJ, Norton LA, Shafer DM, Rossomondo EF. Orthodon-
48. Alhashimi N, Frithiof L, Brudvik P, Bakhiet M. Orthodontic tic force increases tumor necrosis factor-alpha in the human
tooth movement and de novo synthesis of proinflammatory gingival sulcus. Am J Orthod Dentofacial Orthop 1995;108:
cytokines. Am J Orthod Dentofacial Orthop 2001;119:307-12. 519-24.
49. Williams J, Ceccarelli A, Wallace A. Genetic engineering. 2nd 60. Grieve WG III, Johanson J, Moore RN, Reinhardt RA, DuBois
ed. Oxford: BIOS Scientific Publishers; 2001. LM, et al. PGE and IL-1beta levels in gingival crevicular fluid
50. Gorlin RJ, Cohen MM, Hennekam RC. Syndromes of the head during human orthodontic tooth movement. Am J Orthod Dento-
and neck. 4th ed. Oxford: Oxford University Press; 2001. facial Orthop 1994;105:369-74.
51. Schonherr E, Hausser HJ. Extracellular matrix and cytokines: a 61. Helms JA, Schneider RA. Cranial skeletal biology. Nature
functional unit. Dev Immunol 2000;7:89-101. 2003;423:326-31.


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