SPECIAL ARTICLE

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
2006;129:458-68)

L
ife’s complexity and organization are illustrated
in the biological phenomena underlying orth-
odontic tooth movement (OTM). A daunting
array of coordinated biochemical reactions occur in and
around cells, leading to end points of protein synthesis,
mitosis (cell division), and cell differentiation. Mechan-
ically induced, cell-mediated time and space changes in
bone and soft tissue return the craniomandibular system
to homeostasis.
Capability of adaptive response to applied orth-
odontic force rests in the DNA of periodontal ligament
(PDL) and alveolar bone cells. Cell vitality and num-
From the Department of Orthodontics, College of Dental Medicine, Nova
Southeastern University, Fort Lauderdale, Fla.
a
Associate professor.
b
Professor and chair.
Reprint requests to: Richard S. Masella, Department of Orthodontics, College
of Dental Medicine, Nova Southeastern University, 3200 S University Dr, Fort
Lauderdale, FL 33328; e-mail, rmasella@nsu.nova.edu.
Submitted, April 2005; revised and accepted, July 2005.
0889-5406/$32.00
Copyright © 2006 by the American Association of Orthodontists.
doi:10.1016/j.ajodo.2005.12.013
458
bers determine the molecular genetic responses making
tooth movement possible. In the dramatic words of
Kiberstis et al,1 “the robust and unceasing activities of
osteoblasts and osteoclasts imbue humans with the
mechanical prowess to climb mountains or run mara-
thons” and, we add, to undergo orthodontic treatment.
PURPOSE
This article reviews and synthesizes current bio-
medical literature on processes in OTM. It seeks to link
clinical orthodontics with mainstream molecular-ge-
netic research. It does not propose a complete picture
but orients the reader to bases for the bioadaptability of
orthodontic force application and areas where progress
in mechanobiological diagnosis and treatment is likely.
The demands of professionalism require orthodon-
tists to be conversant with biological principles under-
lying treatment. Numerous instances link such knowl-
edge to better patient care.2,3 Roberts and Hartsfield4
even suggested that the importance of bone pathophys-
American Journal of Orthodontics and Dentofacial Orthopedics
Volume 129, Number 4
iology in treatment outcomes requires orthodontists to
be craniofacial bone specialists.
If orthodontists and other dental specialists neglect
the biology of craniofacial bone and attendant thera-
peutic implications, they risk a status closer to techni-
cians than to front-rank health professionals.
Discoveries in the molecular biology and genetics
of bone and connective tissue physiology permit appre-
ciation of the complexity and regulatory sophistication
of OTM.4,5 Yet aspects of biomedical science can
intimidate clinicians. Knowledge of organic chemistry,
biochemistry, and physiology from predental and den-
tal education helps orthodontists understand the behav-
ior of OTM components. Basic chemistry includes
molecular-ionic covalent (electron) bonding, the rela-
tionship between molecular structural change and func-
tional change, and the readiness of cell surface and
intracellular (cytoskeletal) proteins to communicate
with the extracellular matrix (ECM) through receptor-
ligand (binding protein) docking and signaling protein
diffusion or active transport.
GENOMIC REGULATION
A healthy skeleton is a feedback-controlled system
that “continuously integrates signals and responses
which sustain its functions of delivering [systemic]
calcium while maintaining strength.”6 Abundant scien-
tific literature on control of gene expression proves that
this is the era of genomic regulation.6,7 Three years
after the discovery of the human genome structure, the
search is on for controllers of gene expression and
coordination, including those of the skeleton.8 These
are critical issues in adaptive responses provoked by
orthodontic forces.
Michael Eisen of the Lawrence Berkeley National
Laboratory stated that “buried in the DNA sequence is
a regulatory code akin to the genetic code but infinitely
more complicated.”8 Hood et al9 add that “gene regu-
latory networks integrate dynamically changing inputs
from signal transduction pathways and provide dynam-
ically changing outputs to the batteries of genes medi-
ating physiological and developmental responses,” in-
cluding OTM.
DNA, GENES, BASE PAIRING
The DNA in PDL and alveolar bone cell chromo-
somes holds the keys to life and OTM. DNA is divided
into 3 parts: sugar and phosphate “backbone” mole-
cules, and nitrogen-containing cyclic bases.10,11 The
combination makes an extremely reactive molecule.
Regulatory regions of nucleotide (DNA building block)
sequences are scattered within long DNA molecules. A
“gene” is a specific base sequence containing mamy
Masella and Meister 459
3-base codes for long, ordered amino acid chains
(polypeptides or proteins). Genes are made of coding
sequences, “exons,” separated by noncoding sequences,
or “introns.” Knowing the functional significance of
20,000 to 25,000 human genes and regulatory DNA in
23 chromosome pairs, and the possible 100,000⫹
proteins they encode will no doubt provide accurate
definitions of health and disease, and open roads to
improved orthodontic treatment.9,11
The challenge in researching the human genome’s 6
billion complementary base pairs is overwhelming.
Watson et al12 reminded us that the DNA alphabet is
limited to 4 letters: A, T, C, and G, denoting nucleotide
bases adenine, thymine, cytosine, and guanine. In
double-stranded DNA, adenine from 1 strand typically
pairs with thymine from the other; likewise, cytosine
pairs with guanine, a bonding pattern called base
complementarity. If a single letter represents each
nucleotide base, the human genome would make a
million pages of text. A mere 1.1% to 1.5%, or 11,000
to 15,000 pages, are represented by genes.11
Adding complexity is the genome’s lifetime ten-
dency for base sequences to change (mutate) in re-
sponse to genetic-environmental input, defects in
chromosome replication, and unknown reasons. For ex-
ample, cystic fibrosis is characterized by defective cellular
chloride channels, made of mutant proteins encoded by
polymorphic (differently arranged) nucleotide sequences
in the ClCN7 gene.11 Normal chloride channels play a key
role in osteoclastic bone resorption in OTM.13,14 A
thousand polymorphisms discovered in the chloride
channel gene can cause cystic fibrosis. How many total
polymorphisms exist in this and hundreds of other
genes expressed in OTM, and what are their clinical
implications for osteoclastic bone resorption and all
metabolic processes of tooth movement?
SYSTEMS ANALYSIS
The challenge in OTM is understanding systems
rather than components.9 System comprehension, how-
ever, is easier said than done. Although we can see the
entire system, “the information contained in . . . thou-
sands of data points is beyond our ability to interpret
intuitively.”15
The first step in understanding OTM systems is the
collection of a comprehensive expressed messenger
ribonucleic acid (mRNA: DNA gene sequences con-
verted to complementary RNA sequences) transcript
database for osteoblasts, osteoclasts, osteocytes, fibro-
blasts, mesenchymal stem cells (MSCs), cementoblasts,
cementoclasts, and macrophages. Present technology
allows detection of single mRNA transcripts per cell.9
Knowing all mRNA transcripts of pertinent cells means
460 Masella and Meister
knowing all proteins that the system can synthesize.
Protein function is inferred by comparisons with exist-
ing proteomics databases or via experimentation.
For example, osteoblasts and fibroblasts are almost
genetically identical. All genes expressed in fibroblasts
are expressed in osteoblasts.16 Only 2 osteoblast-spe-
cific mRNA transcripts are known: one for the tran-
scription factor (TF, a protein enhancing or suppressing
gene expression) Cbfa1, the other for the TF osteocal-
cin, an inhibitor of osteoblast function. Thus, present
knowledge is that osteoblasts can synthesize only 2 base
proteins that fibroblasts cannot.16
Currently, 96 genes are identified in human osteo-
genesis.17 Functionally, 44 are grouped as growth
factors (GFs), 30 as ECM proteins, and 8 as cell
adhesion molecules. Simultaneous gene expression is
studied in commercially available microarrays that
permit complementary binding and analysis of experi-
mental DNA samples with known DNA sequences.
Despite advances, development of a complete OTM
“parts list” with “parts function” is many years
away.7,18 Linear depictions of signaling pathways fail
to portray 3-dimensional complexity. Even molecular
pathways and networks with relatively few components
“are configured into systems that display complex
behaviors.”5,18 A complete parts catalogue would in-
clude protein-coding and nonprotein-coding genes,
TFs, and mediators of cell-cycle progression and chro-
mosome structure and function. It will also include
many undiscovered functional human DNA sequences.
The magnitude of challenge in delineating genomes
and proteomes is shown in the 20-million-strong
mRNA database generated for normal prostate tissue
and 1 prostate-cancer cell line. Some 300 prostate-
specific genes were identified, along with 554 ex-
pressed TFs.9
PRESSURE-TENSION PERSPECTIVE
Most orthodontists became aware of the role of
cells in OTM in the “pressure-tension theory,” linking
“physiologic” force application with PDL compres-
sional and tensional changes and subsequent activation
of MSCs. The theory proposes that force-subjected
PDL progenitor cells differentiate into compression-
associated osteoclasts and tension-associated osteo-
blasts, causing bone resorption and apposition, respec-
tively.19 “Direct resorption” is associated with light
force application (⫾ 50-100 g per tooth), tissue and cell
preservation, and vascular patency.20 “Indirect (under-
mining) resorption” and hyalinization are associated with
bio-intolerant heavy or necrotizing forces causing crush-
ing injury to PDL tissues, cell death, hemostasis, and
cell-free PDL and adjacent alveolar bone zones.19,20
American Journal of Orthodontics and Dentofacial Orthopedics
April 2006
Molecular genetics of osteoblast differentiation
and function
Although many genes control the complex process
of osteogenesis, the TF Cbfa1 is the earliest expressed
and most specific marker of bone formation.16 Other
bone-forming genes encode proteins for GFs, bone
morphogenetic proteins (BMPs), transforming growth
factor-beta (TGF-␤), and GF-associated internal signal-
ing molecules.21-23Importantly, osteoblast differentia-
tion and proliferation are separate processes controlled
by different genes.24
Expanding the pressure-tension theory, multi-po-
tential MSCs begin differentiating within hours of
orthodontic force application as specialized molecules
are synthesized in the PDL and alveolar bone.25,26
Local osteoblasts and osteocytes express early-response
connective-tissue GF, whereas osteoclasts and osteo-
cytes produce the ECM protein osteopontin.27 Connec-
tive-tissue GF promotes osteoblast precursor prolifera-
tion, mineralization of new bone by mature osteoblasts,
and vasculogenesis.1,27,28
A “paravascular osteogenic response” is noted in
widened (tensional) zones of the PDL and expanded
midpalatal and facial sutures.27 Osteoblast differentia-
tion is a 5-generation process starting with stem-cell
migration from blood vessel walls, or MSC precursor
activation, and preosteoblast formation at about 10
hours postforce. TF genes Cbfa1 (also called Runx-2)
and Osterix help control this process (Fig 1).29,30
(Cbfa1 is also expressed in the osteoblast-homologous,
dentin-synthesizing odontoblast.16,31) The late-acting
TF-coding osteocalcin gene also controls osteoblast
differentiation through an inhibitory effect.32 Other TFs
exerting positive or negative control over osteoblast
differentiation and proliferation will be discovered.
All major GF families help control osteoblast dif-
ferentiation during embryonic development, including
TGF-␤, fibroblast GF-1, and Indian hedgehog.16,28,32
Bone formation begins 40 to 48 hours postforce.27
Regulatory sequences of most genes involved in secret-
ing bone ECM contain 5 to 10-base Cbfa1 binding
sites, which help control bone matrix secretion by
mature osteoblasts.16 The pressure-tension perspective
is enlarged in noting that “bone resorption and deposi-
tion can be present in any tension site, as well as any
compression site.”27,33,34
Other genes participate in mechanically induced
bone modeling, expressing proteins for enzymes nitric
oxide synthetase, prostaglandin G/H synthetase, and
glutamate/aspartate transporter. Parathyroid hormone
helps induce expression of insulin-like GF and estrogen
receptor-beta.27 The recently discovered low-density
American Journal of Orthodontics and Dentofacial Orthopedics Masella and Meister 461
Volume 129, Number 4

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-
trols bone formation through modifying osteoblast
proliferation and increasing bone mass.6,26 LRP5 mu-
tation in both alleles (gene forms) causes loss of
osteoblast function and osteoporosis-pseudoglioma
syndrome, characterized by very low bone mass.6,24
Single-gene mutations in LRP5 might cause gain of
function resulting in osteoblast hyperactivity and in-
creased bone mass. LRP5 might mediate other molec-
ular genetic processes, including cancer.6
Mutations in any OTM-associated gene induce
mutant, missing, insufficient, or excess proteins and,
without genetic redundancy, will alter clinical response.
The more extensive the single gene mutation or number
of mutant genes, the greater the clinical deficit.
Osteoblasts contain a rich array of functional cell
surface receptors open to protein docking. BMPs bind
to such receptors, triggering a signaling pathway that
promotes osteoprogenitor cell differentiation and up-
regulation (increase) of osteoblast function.35-37 BMPs
can induce Cbfa1 expression. In turn, BMP expression
and signaling might be controlled by signaling mole-
cules and Hh genes and proteins.32,36,38 Growth hor-
mone promotes bone formation through ligation with
GF receptors on osteoblast surfaces and stimulation of
insulin-like GF-1.39
Osteoblast receptor-ligand docking not only changes
cell form and function and initiates signaling, but also
serves as a potential point of therapeutic modification.
Drugs that enhance or block activity of osteoblast
receptors are under investigation.
Finally, a family of molecules known as “ho-
meobox” proteins (specialized DNA sequences in ex-
ons of many regulatory genes) also help control osteo-
blast differentiation. Msx1 protein is a key modulator
of bone development and modeling, participating in
embryologic body patterning and skeletal adaptation in
adulthood.16 Msx2 could be another regulator of Cbfa1
expression. The homeobox protein Hoxa-2 controls
second branchial arch patterning and might suppress
both Cbfa1 expression and bone formation.
NEUROTRANSMITTERS
Somatosensory neurons transmit signals from pe-
ripheral tissues to the central nervous system (CNS).
An example of component multi-functionality is the
discovery of the efferent (output) function of afferent
(input) neurons: release of biologically active proteins
that contribute to neurogenic inflammation. Increased
concentration of these PDL neuropeptides during OTM
indicates their importance.40,41
462 Masella and Meister
With application of physiologic orthodontic force,
PDL peripheral nerve fibers release calcitonin gene-
related peptide (CGRP) and substance P.40,41 Other
undiscovered neurotransmitters might mediate the in-
flammatory process. Besides acting as neurotransmit-
ters, CGRP and substance P serve as vasodilators,
inducers of increased vascular flow and permeability
(diapedesis), and stimulators of plasma extravasation
and leukocyte migration into tissues (transmigration).
A work-horse molecule, CGRP, induces bone forma-
tion through osteoblast proliferation and osteoclast
inhibition.42-44
Receptors for CGRP are found on osteoblasts,
monocytes, lymphocytes, and mast cells. Receptor
activation (docking) results in amplified 2-way inter-
cellular communication, promoting cytokine (inflam-
matory mediator molecule) synthesis and release.41,42
Cytokine receptors on neuropeptide molecules facili-
tate cellular cross-talk and synthesis of other molecules
that change cell behavior. Signaling pathways change
mechanical force into molecular events (signal trans-
duction) and tooth movement.45 At least 10 networked
signal transduction pathways participate in OTM. Dam-
age to any signaling pathway can cause dysfunction and
disease.
Normal PDL and alveolar bone innervation is
essential to OTM-associated periodontal remodeling.
Healthy innervation promotes maximum blood flow
during OTM, whereas denervation reduces blood flow
and bone formation.46,47
Systemic factors such as age, nutritional status,
drug history, and metabolic bone diseases might alter
key molecules that mediate mechanically induced lo-
calized inflammation, bone modeling, and homeostatic
bone remodeling.27
Osteoclast differentiation and function
Osteoclasts are specialized multinucleated giant cells
that develop from monocyte-hematopoietic cells.13,14
Their unique properties include adherence to bone
matrix and secretion of acid and lytic enzymes that
destroy mineral and protein structures.13 At least 24
genes and 60 proteins are implicated in positive and
negative regulation of osteoclastogenesis and osteoclast
function. A series of TFs controls osteoclast differen-
tiation.14,26
Roberts et al27 considered bone resorption at the
PDL surface the rate-limiting step in OTM. Harada and
Rodan6 specified osteoprotegerin (OPG), cathepsin K,
and chloride channel 7 (ClCN7) as rate-limiting agents
for osteoclast differentiation and function (Fig 2). OPG
blocks the TF receptor activator of nuclear factor
kappa B (RANK) and RANK ligand (RANKL) dock-
American Journal of Orthodontics and Dentofacial Orthopedics
April 2006
ing, cathepsin K destroys bone matrix proteins, whereas
chloride channel 7 maintains osteoclast neutrality by
shuffling chloride ions through the cell membrane.
These molecules are also targets of drug discovery.
A patient’s bone resorption potential and timely
OTM outcome then depend on recruitment of mature
osteoclasts and precursors, osteoclast differentiation,
and numbers of functional osteoclasts at the bone-PDL
interface. Clinical success also hinges on normal oste-
oclast and osteoblast genes that correctly express
needed proteins in adequate amounts at the right times
and places, including regulatory molecules such as
tumor necrosis factor and its receptor, colony stimulat-
ing factor-1, OPG, and RANK and RANKL.27
The earliest marker of bone resorption could be the
cytokine interleukin-1beta (IL-1␤). A mutant gene of
IL-1␤ might be associated with down-regulation of this
important cytokine.27 Osteoclastic bone resorption is
also facilitated by PGE2, nitric oxide, IL-6, and other
inflammatory cytokines.48
RANK and RANKL are key proteins regulating
osteoclast function.13,14,24,27 Synthesis of RANKL by
osteoblasts and its lifetime role in promoting osteoclast
differentiation supports the idea that osteoblasts control
only osteoclast differentiation, not function.24 How-
ever, an osteoclast-originating messenger molecule was
recently discovered that appears to “talk” with osteo-
blasts. This underscores the biologic concept of contin-
ual, 2-way cell-to-cell communication.2
Bone resorption is a much faster process than bone
apposition; it can take 3 months to replace bone
resorbed in only 2 to 3 weeks.27 The molecular genetics
of osteoclast differentiation and function might be
simpler than that of osteoblasts.
Endocrine regulation of bone physiology
Sex steroids also influence bone homeostasis (Fig 3).
Estrogen suppresses bone resorption by reducing oste-
oclast numbers.6 Testosterone reduces bone resorption
in males, promotes bone formation in males and fe-
males, and can be converted to estrogen to inhibit bone
resorption. Much remains to be learned about estrogen-
mediated bone resorption.24
A central nervous system component is another
regulator of osteoblast function. The hormone leptin is
synthesized by fat cells and acts by binding to signal-
transduction receptors on hypothalamic neurons.16
Through “hypothalamic relay,” leptin strongly inhibits
bone formation by suppressing osteoblast function
(neuroendocrine control).24 Peripheral signaling is me-
diated by the sympathetic nervous system. When leptin is
absent because of adipocyte depletion, as in generalized
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
thought to have many target organs and functions.16
The proteome
Cellular biochemistry is carried out by proteins.
Proteins commonly function in concert with other
proteins in complexes or networks.9 Liebler advised
that “each protein, whether a transmembrane receptor,
transcription factor, [or] protein kinase, expresses a
function that assumes significance only in the context of
all the other functions and activities also being expressed
in the same cell (italics added).”15 He also references the
“thousands of genes that may be expressed in each cell in
varying combinations (italics added).”15
The level of molecular coordination within and
outside cells is believed to be ultracomplex. Posttrans-
464 Masella and Meister
Fig 3. Hormonal control of bone formation and resorption.
lational modification (after ribosome-based synthesis)
of proteins is an important point of functional change
and increased protein versatility.11,15,49 Phosphate
(HPO3-, phosphorylation) and methyl groups (-CH3,
methylation), other ions, and lipids might bond to
base proteins. Protein modification results in changed
3-dimensional shape (conformation), bonding poten-
tial, pattern of molecular folding, and molecular func-
tion.10,11,15 Gorlin et al50 referred to “molecular parsi-
mony” in describing the ubiquitous multi-potentiality,
or pleiotropy, of human genes and protein products.
Another rich source of human protein variability is
“alternative splicing” of primary mRNA. One gene can
produce mRNA transcripts that differ in structure
(differentially cut by splicing enzymes) and therefore
coding potential.4,11,15,49,50 The fibronectin gene com-
monly expressed in OTM is an example. The ECM
protein fibronectin is a mediator of cell-ECM inter-
action. Differential mRNA splicing produces many
forms of fibronectin (isoforms), each with a specific
function.49,51
Intracellular and extracellular environments
Orthodontic force-induced system adaptation oc-
curs in the context of 5 related microstructures: PDL
American Journal of Orthodontics and Dentofacial Orthopedics
April 2006
and alveolar bone ECM, cell membrane, cytoskeleton,
matrix of nuclear proteins, and genome (Fig 4).
Orthodontic force causes physical distortion of
PDL and alveolar bone cells and the ECM, triggering
many biochemical reaction cascades that affect all 5
micro-entities.52 ECM and cell distortion initiate struc-
tural and functional changes in extracellular, cell mem-
brane, and cytoskeletal proteins. At the same time,
numerous submembrane proteins associate in “cellular
focal adhesions.” These complex structural/functional
adaptations transmit survival and growth signals to the
cytoplasm and help mediate cell adhesion via integrin
activation.53 A regulator of integrin-mediated focal
adhesions is the enzyme focal adhesion kinase. Illus-
trating molecular parsimony, focal adhesion kinase
also regulates cell growth, migration, proliferation,
and survival. Protein phosphorylation mediated by
protein kinase enzymes is important in all aspects of
biology.53-55
Subsequent changes in cytoskeletal protein struc-
ture and function, such as activin polymerization and
depolymerization, continue the signaling process, which
can also involve molecular-ionic diffusion outside cells,
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
RNA.

transcytosis through cells, or released cell-membrane
vesicles.38,56
Signal input, genetic output
Cytoplasmic signaling proteins Hh, sonic hedge-
hog, the TGF-␤ superfamily, and many TFs and ions
(Ca⫹⫹, PO3-) reach the nuclear matrix and then
genome, resulting in enhanced or suppressed gene
expression. Input becomes output as gene-expressed
proteins, or protein synthesis inhibition, mobilize mi-
tosis, cell motility, secretion of other proteins, and
programmed cell death (apoptosis) that further modify
cytoskeleton, cell membrane, and ECM.52 The process
is continuous (Fig 4).
Changes in cell environment (development, aging,
external conditions) might also change the patterns of
gene expression.11 Epigenetic regulation of gene ex-
pression involves heritable changes not from DNA base
sequence changes but from chemical modification of
bases ATCG or TFs bound with DNA. Such genomic
changes can occur throughout life. Hartl and Jones11
emphasized that there is “a great deal to be learned
about molecular mechanisms underlying epigenetic
modifications.”
PDL and alveolar bone cell death and renewal
Apoptosis is a critically important process in skel-
etal maturation, adult bone remodeling, and bone re-
pair.25 In health, a close linkage exists between bone
cell proliferation, differentiation, and apoptosis, result-
ing in an adequate pool of osteoblasts and osteoclasts
for bone homeostasis.22,25,57
In reducing osteoblast numbers through apoptosis
and thereby decreasing bone formation, the SOST gene
is an important regulator of bone remodeling.21-25,27,29
Located in chromosome 17q12-q21 (long arm, region
1-2 below centromere to region 2-1), SOST expresses
the protein sclerostin, a BMP-antagonist and signaling
inhibitor.6,21,25,27 The Cbfa1 gene is part of the SOST
gene promoter.29 Therapeutic agents blocking the ac-
466 Masella and Meister
tion of sclerostin might allow restoration of osteopo-
rotic bone.
The many proteins involved in signal transduction,
TF control, and cell cycle regulation are rapidly de-
graded after use as a means of regulating their activi-
ties.11,15
Progress in diagnosis and treatment
Interpatient variability in mechanical response is
common in orthodontic practice. Reasons can include
differences in PDL and alveolar bone cell numbers and
genomes, including genes for signaling proteins; num-
bers of white blood cells, GFs, and cytokines per
volumetric measure of tissue-blood; alveolar bone min-
eral density; and PDL and alveolar bone vascularity per
volumetric tissue measure.
The ENCODE (ENCyclopedia Of DNA Elements)
project has started identifying “all structural and func-
tional elements of the human genome.”58 This and
much other research will eventually permit correlation
of patient genotype with clinical presentation and
laboratory-derived protein profiles. This will allow
orthodontists to identify biological promoters and in-
hibitors of OTM and plan molecular intervention to
maximize adaptive response.
If gene expression in tissues subjected to mechan-
ical force shows patterns of alteration in secreted
proteins in blood or gingival crevicular fluid, perhaps
these media can serve as windows for diagnosis and
prognosis, and sources of active-treatment biomarkers
for assessing mechanics.48,59,60
On another front, embryology shows that the PDL,
alveolar bone, dentin, and dental pulp are neural-crest
derivatives.61 A short step is identification of undiffer-
entiated adult neural-crest cells from marrow spaces
and pulp as candidates for resolution of craniofacial
skeletal and dental defects. Discovery of molecular
signals that induce stem-cell differentiation and cell-
delivery methods are necessary elements. A roadblock
to stem-cell enhancement, as with gene engineering, is
inability to selectively target deficient genes, cells, and
tissues. Yet, as Helms and Schneider61 state, “cellular
and molecular therapies, rather than [brackets, arch-
wires], handpieces and scalpels, may one day be used
by [orthodontists and] dentists to treat [craniofacial]
afflictions.”
CONCLUSIONS
We communicate with PDL and alveolar bone cells
in applying orthodontic forces to teeth and bones. In
providing genomic-derived layers of networked bio-
chemical processes to meet homeostatic-disturbing
orthodontic mechanics, these cells enable bone re-
American Journal of Orthodontics and Dentofacial Orthopedics
April 2006
sponse, tooth movement, and return to homeostasis.
PDL and alveolar bone cells are sensitive environment-
to-genome-to-environment communicators, and the
brain and heart of OTM.
The following biological concepts are noted:
1. Gene-directed protein synthesis and modification,
and integration of many proteins, form the essence
of all life processes, including OTM.
2. PDL and alveolar bone cells provide hundreds of
genes and thousands of proteins for OTM.
3. Bone adaptation to orthodontic force depends on
normal osteoblast and osteoclast genes that cor-
rectly express needed proteins in adequate
amounts at the right times and places.
4. PDL and alveolar bone cells constantly “talk” via
molecular messengers or signaling. Communica-
tion is a 2-way process.
5. Healthy and pathological bone metabolism in-
volves many interactions between genetic and
environmental (epigenetic) factors. This adds to
the challenge of understanding bone pathophysi-
ology.6
6. The molecular genetic processes underlying OTM
function as a feedback system of checks and
balances. Activator molecules beget suppressor
molecules and return to steady state.
7. OTM biology can be envisioned in the physical
context of PDL-alveolar bone ECM, cell mem-
brane, cytoskeleton, nuclear matrix, and genome,
giving a relatively broad perspective on location
and flow of processes critical to adaptive response.
8. Receptor-ligand docking is a potent and common
initiator of signal transduction of mechanical
forces into molecular events and OTM. It is also a
discovery target for bone-enhancing drugs.
9. Despite identification of many regulatory mole-
cules, the genetic mechanism of “orchestrated
synthesis,” or how genes and molecules work in
concert through DNA “command centers” to in-
duce and coordinate cell mobility, differentiation,
proliferation, function, and apoptosis, “still re-
main[s] largely unknown.”61
10. Identification of mutations in OTM-associated
genes of orthodontic patients, especially those
driving osteoclast proton pumps (mineral matrix
acidification) and chloride channels, and osteo-
blast-derived mineral and protein matrices, will
permit gene therapy to restore normal matrix and
protein synthesis and function. Achieving cell and
tissue selectivity in repairing mutant genes with
engineered DNA sequences, or in using stem cells
to grow craniofacial tissues, is a major obstacle.
American Journal of Orthodontics and Dentofacial Orthopedics
Volume 129, Number 4
These therapies are perhaps 10 to 15 years away in
everyday orthodontics.
11. Interpatient variation in mechanobiological re-
sponse is most likely due to differences in bone
and PDL cell populations, genomes, and protein
expression patterns.
12. Orthodontic treatment probably will evolve into a
combination of mechanics and molecular-genetic-
cellular interventions: a change from shotgun to
focused communication with OTM cells.8
We thank Drs Roberto Carvalho, Ze’ev Dav-
idovitch, J. K. Hartsfield, Jr, and W. E. Roberts for their
insights, inspiration, and graciousness.
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