thinking beyond the wire: emerging biologic relationships in orthodontics and

8/14/2019 Thinking Beyond the Wire: Emerging Biologic Relationships in Orthodontics And

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Thinking Beyond the Wire: Emerging BiologicRelationships in Orthodontics andPeriodontology

Richard S. Masella and Ping-Lin Chung

Orthodontic tooth movement (OTM) is a biologic event. It involves a seriesof sophisticated signal transduction processes that result in alveolar boneremodeling. Interplay of the gene expression activities between osteoblastsand osteoclasts regulate the alveolar bone adaptation to orthodontic forces.

The mechanisms that sense and translate the mechanical stimulus intomolecular events have remained a puzzle to current scientists for a longperiod of time. The mechanosome is a recently discovered cytoplasmiccommunication mechanism that can possibly explain the signaling betweentreatment and the bone cell response. That is, it may detect mechanicalloads and in turn activate the downstream nuclear gene expression. Ad-

vancement in molecular biology is likely to make the manipulation of boneremodeling and control of tooth movement easier and more predictable inthe future. Pharmaceutical intervention and genetic enhancement are ex-

amples of clinical applications promised by current researchers in basicscience. This article reviews the biomedical literature and plots the trendin understanding the biochemical basis of OTM to date. Future dentofa-cial orthopedists will likely integrate both conventional orthodonticmechanotherapy and applications of molecular biology in orthodontictreatment suggested by concepts in this article. (Semin Orthod 2008;14:290-304.) 2008 Published by Elsevier Inc.

Engineered alveolar ridge topography andbone regeneration are commonly used byperiodontal specialists to repair alveolar bonedefects damaged by disease. Some of the indica-tions include periodontal attachment (bone)maintenance, postextraction socket regenera-tion, and implant site preparation. However, lossof vertical bone height (attachment loss) as a

result of periodontal disease is often difficult toovercome with hard tissue grafting alone. Evenwhere successful the outcome is often unpredict-able.

However, orthodontic tooth movement (OTM),as demonstrated by clinical findings,1-3 is an al-ternative method to induce bone regenerationand morphotype modification through force-mediated remodeling. More importantly, orth-odontics has recently become an important ad-junct to implant dentistry because orthodontistscan open edentulous spaces for implant place-ment. Preimplant orthodontics has also beenperformed to generate alveolar bone height atperiodontally compromised areas. Gunduz andcoworkers have shown that bodily tooth move-ment into an edentulous area with a transverselythinned alveolar ridge resulted in therapeuticbone remodeling.1 A dental implant could thenbe placed into the orthodontically developed

Adjunct Professor of Education Nova Southeastern Univer-

sity, Fischler School of Education and Human Services, BoyntonBeach, FL.Resident, Advanced Graduate Orthodontics, Department of Devel-

opmental Biology, Harvard School of Dental Medicine, Boston, MA.Address correspondence to Richard S. Masella, DMD, Adjunct

Professor of Education, Nova Southeastern University, FischlerSchool of Education and Human Services, 3830 Edgar Ave, Boyn-ton Beach, FL 33436. Phone and Fax: (561) 737-8193; E-mail:[email protected]

2008 Published by Elsevier Inc.1073-8746/08/1404-0$30.00/0doi:10.1053/j.sodo.2008.07.006

290 Seminars in Orthodontics, Vol 14, No 4 (December), 2008: pp 290-304
mailto:[email protected]:[email protected]


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edentulous site. A case report by Biggs and Bea-gle showed that orthodontic intrusive and extru-sive forces were exerted on hopeless teeth togain alveolar bone height in the future implantsite.3 Orthodontic alveolar site development is

also employed in the replacement of congeni-tally missing maxillary lateral incisors with sin-gle-tooth implants. The permanent canines aremoved distally after being allowed to erupt me-sially when lateral incisors are congenitally ab-sent. Adequate alveolar ridge width will then beestablished for future implants.3

These newly emphasized clinical phenomenasuggest that facial and alveolar bone may not beas immutable as previous generations of dentistswere taught. The aim of this article is to presentmolecular and tissue level biochemical conceptsthat might explain exactly how this newly de-scribed bone malleability can occur and provokethe reader to innovative solutions to physicaland intellectual limits that have challenged ourspecialty for a century.

Histochemical Perspectives

Contrary to some popular perceptions, thera-peutic tooth movement is not essentially a func-tion of Newtonian mechanics. Tooth movementis a biologic event, in fact encompassing a cas-cade of histological and biochemical reactions.

Once the mechanical stimulus is applied, a phe-nomenon referred to as signal transduction con-verts mechanical strain to biochemical events. Forthe 21st century clinician, only a biologic orien-tation can capture the full scope of orthopedictissue engineering concepts that often escapeour consciousness when we preoccupy ourselveswith mechanical manipulation or the cosmeticenhancement of individual teeth for popularand even fatuous affectations. In fact, an over-emphasis on superficial cosmetic mechanics, ig-noring a century of scientific theory, in the long

run can produce severe biologically harmfultreatment outcomes for the patient. Thus, theperiodontal biologic message to all orthodon-tists, especially in the treatment of a motherschild, is one of profound and prudential cau-tion. This begins with respect for health of thegingiva and periodontal ligament (PDL).

The PDL is generally considered a specializedconnective tissue responsible for the dramaticalveolar bone remodeling process. Yet, applica-

tion of orthodontic force triggers remodelingresponses far beyond the ligament. Bone remod-eling consists of interplay between osteoclasticresorption and osteoblastic deposition (new boneformation). In general, bone remodeling and

modeling can occur by a kind of spatial driftthat adds new bone tissue on one side of thecortex and takes it away from the contralateralcortex. (These are not fundamentally new con-cepts, but merely embellished. See a classical,nuanced review by Roberts WE, in Graber T,Vanarsdall R, Vig K, eds: Orthodontics: CurrentPrinciples and Techniques. 4th ed. St. Louis,Mosby, 2005.) According to Enlow, the perios-teal surface receiving new bone in the directionof the OTM vector undergoes deposition andthe periosteal surface origin of the vector under-

goes resorption.4

Yet, the PDL and cribriformplate activity have been traditionally character-ized quite the opposite, with resorption and dep-osition occurring on the pressure and ten-sion side of the ligament, respectively. Thereconciliation of this conceptual dissonance liesin viewing the alveolus as a whole bone and thePDL-cribriform plate complex as analogous toendosteal surfaces.

Two proposed classical mechanisms attemptto explain the bone physiology reaction to stress:the popular but simplistic pressure-tension

construct and the bioelectric theories. Thepressure-tension model proposes the tooth aslying in a connective fiber sling attached to thesocket, with fiber stretch (tension) eliciting os-teogenesis and fiber compression eliciting oste-oclastic resorption on the PDL side (frontal re-sorption) or endosteal side (undermining orrear resorption) of the cribriform plate de-pending on pressure gradients. While easy tounderstand in a grossly mechanical way for pa-tients, it fails to respect myriad biochemical re-sponses by the cells and extracellular matrix

(ECM) of the PDL and alveolar bone.

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The bio-electric theory relates tooth movement to themovement of charged particles produced whenalveolar bone is flexed. Specifically this refers tohydroxyapatite crystals (immediate and rapidlydissipating piezoelectric potential) and theslower ionic flux at fluid-solid interfaces withinthe living osteocyte-cannaliculi syncytium.6 Po-tential differences created by forcing thesecharged particles or electrolytes through narrow

291Orthodontic Tooth Movement, Orthodontics, Periodontology


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channels within the bone are streaming poten-tials.7

At this juncture, it is probably appropriateto avoid falling into a common misconception.Neither theory completely explains the OTM

phenomenon; both theories are involved inthe biologic control of tooth movement. Thus,integration offers insights into techniques thatmay allow the dentofacial orthopedist to engi-neer an optimal response of bone with asmuch alacrity as the holy-grail search for anelusive optimal force. Contemporary clinicaland basic science research suggests this may beachieved through such seemingly disparatemethods as electromagnetic manipulation,8 sur-gical provocation to accelerate OTM,9 genetictesting and enhancement,10 or even pharmaco-logic supplementation in situ.

Pressure-Tension Model

A more detailed pressure-tension theory statesthat chemical signals stimulate cellular differen-tiation and ultimately tooth movement. Whenorthodontic forces are applied to the tooth, andafter capillary damping of initially applied force,extracellular fluids of the PDL, a viscoelastic gel,shift distorted cells and ECM. This force altersblood flow within the PDL, namely blood flow ismaintained or increased where the PDL is under

tension and restricted in areas of pressure. Mi-gration of leukocytes into the extravascularspace (a mild, aseptic inflammation) occurs inareas of both tension and pressure through dif-ferent mechanisms. Blood flow is decreasedwhere the PDL is compressed. The alterations inblood flow induce chemical changes, directlyand indirectly through chemical messengers.This process of signal transduction, a biologi-cal event, is what proximately stimulates cellulardifferentiation and bone remodeling, thus facil-itating tooth movement.

The reader should bear in mind that thepressure/tension model may be inaccurate tothe extent it is oversimplified and generalized.In common use it emerges as a rarefied theorythat may have little predictive power since thePDL is roughly 0.25 to 0.33 mm wide, a dimen-sion smaller than a wire activation seeking togain the usual rate of activation to elicit theexpected 1 mm of tooth movement per month.This observation suggests a need to widen the

conceptual horizons of orthodontic therapy, tak-ing it from a strict Newtonian mechanical mod-els (bias) to incorporate biochemical conceptsand the burgeoning science of tissue engineer-ing.

Bioelectric Model

The PDL histological model that cannot fullyexplain tooth movement must be supplementedwith physical, chemical and molecular biologicconcepts of biomechanics if OTM is to be fullyand accurately conceptualized in a modern sci-entific context. The bioelectric theory claimsthat movement of charged particles may alsoplay a role in tooth movement. Two types ofcharge movement proposed by researchers in-clude piezoelectric and streaming potential sig-nals.7

In terms of physical mechanics, the piezoelec-tric effect is a phenomenon where an electricpolarity is created in crystals when deformed.(When a bone crystal is compressed, tissue ionsin the surrounding fluid also migrate along theeasiest axis pathways.) The net movement ofnegative charge in the crystal in one direction isenhanced by the movement of positive charge inthe opposite direction, creating a net dipolemoment. The displacement of electron densityleads to a voltage across opposite sides of the

crystal, and to an electric current if a conductivematerial connects the opposite sides. Thus, anelectric current can be generated between thetwo oppositely charged surfaces of each crystaland can flow from one part of the crystal latticeto another, creating piezoelectric signals.

Piezoelectric effects were initially thought tobe materially effective signals responsible fortooth movement because bone consists of aninorganic phase of hydroxyapatite crystals andorganic phase of mainly type I collagen. When aforce is applied against bone, these hydroxyap-

atite crystals bend due to the elasticity of theorganic collagen phase, creating a piezoelectriceffect within the bone. However, piezoelectricphenomena are brief and effete and should notbe conflated with the longer lasting and appar-ently more influential ion flux that occurs simul-taneously in tissue fluid.

Many studies have shown that dry bone doesindeed undergo a piezoelectric effect7; however,in vivo, bone is very complex tissue and is sur-

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rounded by a wet environment. When chargedions or electrolytes within solution are forcedthrough a narrow channel, the term streamingpotentials more accurately portrays the bioelec-tric signals or potential differences created

along that channel. While certain ions of thesame sign are attracted to the channel walls,other charged ions of opposite charge becomeconcentrated in the remaining fluid that ispassing through. Osteocyte cell processes incannaliculi apparently communicate at a gapjunction. These types of signals are somewhatanalogous to action potentials through nerves atsynapses. Thus, the mechanotransduction sys-tem, the osteocyte-cannaliculi syncytium, facili-tates cell-to-cell communication as the ion fluxoccurs from fluid movement within the Haver-sian systems (osteons) in bone under variablestrain.7

The bioelectric theory incorporates both thepiezoelectric and the streaming potential typesof potential differences and ionic movement,implying that structural alterations throughoutthe bone are conducted and/or triggered byionic charge differences. Thus, when an orth-odontic force is applied to the tooth, the toothpushes against the bone, bending the crystallinestructure of alveolar bone and collagen and tis-sue fluid far beyond the PDL.11,12

Electric stimulation can enhance cellular en-

zymatic phosphorylation activities in periodon-tal tissues and may be a potentmethod in accel-erating alveolar bone turnover.8 Therefore, intheory, electric and electromagnetic influencescan modify the bone remodeling involved inOTM, even when externally applied as therapeu-tic adjuncts to healing as demonstrated in theelectric braces research of Davidovitch and co-workers.8

Contemporary Concepts

The Baumrind Model

The research conducted by Baumrind and co-workers gave orthodontists an interesting perspec-tive on OTM as early as 1965.13,14 In contrast to thepressure-tension theory of Schwarz,15 Baumrindproposed that the PDL is a continuous hydrostaticsystem; any force delivered to it will be transmittedequally to all regions of the PDL. Such a modelrefers to a kind of viscoelastic system, recalling

Pascals law, which states that when there is anincrease in pressure at any point in a confinedfluid, there is an equal increase at every otherpoint in the container. Differential stresses andstrains in the periodontium can therefore only

be developed at the interface of more solidparts: bone, tooth, the collagen fibers of thePDL, and the surrounding alveolus and facialbones. This perspective calls for a wider concep-tualization to explain OTM more accurately withemerging histometric, biochemical, cellular ge-netic, and molecular biological concepts.16

Also, Baumrind found that bone deflectioncan be produced routinely by forces lower thanthose required to produce consequential changesin PDL width. This further strengthens his pointthat seeing the PDL as a viscous gel system may bemore productive in everyday clinical practice. Iffluid in the periodontium were to be squeezedout in one region by orthodontic force, it wouldhave to be squeezed out in all regions, thusproducing an immediate damping phenome-non. He also questioned the observation of un-dermining resorption in pressure-tension the-ory, since similar marrow space activity is alsoobserved in the tension side of the periodontalligament during OTM.

Baumrind therefore proposed an alternativehypothesis: When orthodontic appliances areplaced, forces delivered to the tooth are trans-

mitted to all the tissues in the region of forceapplication.14 All three structures, tooth, PDL,and alveolar bone, are deformed. The amountof deformation (measured as microstrain) is de-termined by the elastic properties (elastic mod-ulus) of each tissue component. In contrast tothe narrow pressure-tension model, remote ar-eas of bone may be involved in tooth movementas Melsen suggested in 200111; the results oforthodontic intrusion could be perceived asbending of alveolar bone produced by the pullfrom Sharpeys fibers.

Further Reductionist Analysis

Piezoelectric effects and the pressure-tensionmodels suggest that when the mechanical forceon bone is removed, the once-loaded systemreverts back to its original homeostatic or steadystate of dynamic equilibrium. However, it shouldbe remembered that studies from Johnson statethat the effects of forces on the bone are trans-



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duced into another form in which a biochem-ical cascade remains activated long after themechanical stimulation has been removed.12

These studies report that strain-induced fluidflow stimulates the production and/or release of

various bioactive substances, including potentmorphogens, directly from osteoblasts and osteo-cytes. Coincidentally, these substances include sec-ond messengers and inflammatory mediatorsmentioned previously, namely prostaglandin E2(PGE2), inorganic phosphate 3 (IP3), calcium, cy-clic adenosine monophosphate (cAMP), and ni-trous oxide (NO), a particularly important mor-phogen in osteoblasts and osteocytes. Specifically,NO is shown to regulate bone remodeling by in-hibiting resorption and by possibly stimulating os-teoblastic proliferation. This is important becausea recent animal study suggested a more optimalresponse (enhanced osteoclasia) can be engi-neered by injecting L-arginine, an NO precursor,in situ during OTM.16 NO also exerts effects withinendothelial cells, causing vasodilation of blood ves-sel walls, resulting in multiple and variable cellmigration and differentiation. Thus, osteoblastsand endothelial cells both respond to fluid flowsimilarly, and therefore, both play a role at themost fundamental molecular level in mediatingbone remodeling through altering the dynamicbalance between osteoblast and osteoclast activi-ty.16

Functional Matrix Hypothesis of Moss

A fundamental epistemological schism has plaguedorthodontics for nearly a century. This is not idleinternecine or ideological bickering because thepolar philosophical truths can have profoundclinical ramifications such as extracting teeth, flat-tening facial profiles, or risking gingival dehis-cence on teeth in growing children. The vexingquestion is whether the alveolar form in any onepatient is fundamentally immutable in health and

disease or whether alveolar bone, like liquids orgels in a container, assumes the shape of its con-taining matrix following the movement of theteeth. Moss17 nicely synthesizes these aforemen-tioned concepts and orchestrates them into thefunctional matrix hypothesis (FMH), arguing thatshape and dimensions of alveolar bone, throughsingle-generation phenotypic plasticity, can indeedbe defined by a functional matrix (container),the dental roots. If he is correct then teeth may be

moved beyond a restricted limit of malocclusionwith relative impunity. While clinical data demon-strate that this may be possible, especially in thetransitional dentition, others contend that movingteeth off the alveolar housing risks bony and

ultimately gingival dehiscence. Fortunately, re-searchers have observed that in monkeys reappo-sition of labial bone can occur in a coronal direc-tion after teeth in extreme labial position withbone dehiscence and consequent gingival reces-sion were moved to a more normal position.18

Several variables play a role in his hypothesis:(1) the skeletal or bone units and the functionalmatrices (the nonskeletal remainder includingthe related cells, tissue, organs, fluid, and evenspaces); (2) the hierarchy of bone organizationranging from the level of the whole skeleton(higher attributes) to the level of a single bonecell (lower attributes); and (3) the intrinsic(genomic) and extrinsic (epigenetic) factors. Allthree variables contribute to the entire skeletalsystems development and adaptation to func-tional loads.

Moss stated that the lower attributes of singlebone cells cannot predict the higher attributesof the whole skeleton or bone tissue in the hier-archy of bone organization. G.D. Singh, relyingon the accuracy of finite element analysis meth-odologies, elaborates on the FMH by asking usto view spatio-temporo matrices as affecting mor-

phogenesis in an attempt to achieve a structuralbalance and physiologic tissue homeostasis. Histerm for this natural adaptive phenomenon isthe spatial matrix hypothesis (SMH).19 We pro-pose that the modern orthodontic clinicianshould consider a coherent, comprehensive,and fully integrated theoretical systems ap-proach that appreciates the biology from theintracellular biochemical dynamics of singlebone cells, through tissue level interactions, tothe clinical changes we induce in skeletal formgrossly.

This concept has been shared by medicalphysiologists and orthopedists for many yearsunder the rubric Utah Paradigm of Bone Physi-ology.20 This model suggests that a nephron-equivalent entity called the basic multicellularunit (BMU) is largely responsible for regionalbone remodeling. Wilcko and Ferguson9 havepresented compelling evidence and clinicalstudies of dentoalveolar surgical techniques thatdemonstrate this phenomenon at work in a very



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meaningful and clinically practical way. Theycite the regional acceleratory phenomenon(RAP) of medical orthopedist, H.M Frost, as theessential operative physiologic mechanism re-sponsible for their astonishing clinical revela-

tions and stable treatment outcomes.The surgical techniques included buccal and

lingual full-thickness flaps, a kind of scarificationof the cortical plates (selective decortication),concomitant bone grafting/augmentation, andprimary flap closure. Their treatment of Class Icases of severe crowding and constricted maxil-lary alveoli were completed in approximately 6months. They suggested that the incorporationof the bone augmentation into a decorticationsurgical protocol makes it possible to completethe orthodontic treatment with a more intactperiodontium. As a workable, pragmatic clini-cal guideline, the Utah Paradigm developedthrough the collaboration of Drs. Harold M.Frost and Webster S.S. Jee, conceptually compat-ible with Baumrinds model, explains and pre-dicts OTM behavior in the larger periodontalcontext in a manner superior to the classic pres-sure-tension construct. Thus, the best course forthe clinician is a full integration of all theoriesbecause even the novel approach of the Wilcko-Ferguson studies may depend on intrinsic bio-chemical mediators to enhance the effects ofnatural ligands or pharmaceutical agents such

as recombinant bone morphogenetic protein(rhBMP-2).

Williams, Singh, and Damon have also al-luded to principles that mimic both the RAP andFMH in their nonsurgical approaches to alveolarand dentofacial orthopedic therapy, osteoblas-tic recruitment, spatial matrix, and physio-logically adaptive force, respectively.21

While enterprising clinical innovators andkeen scientific observers, they are not initiatorsof this concept, because according to Melsen,the woven bone formation seen ahead of alve-

olus in the direction of the movement could beinterpreted as an expression of RAP.11 Accord-ing to Frost, any regional noxious stimulus,chemical, surgical, or mechanical, of sufficientmagnitude can evoke RAP.22 The extension ofthe affected region and the intensity of the res-ponse vary directly with the magnitude and thenature of the stimulus as long as it occurs abovea minimal effective strain (MES), the borderlinestrain below which appropriate bone modeling

does not occur. The daunting clinical challengefor each practitioner is to become sensitive tothe fact that strain for each patient in a widelybiodiverse biological and psychosocial milieu.This is where an understanding of biochemistry

sharpens the minds eye to see and think be-yond bends in a wire.

Observing this at the biochemical and molec-ular level, a single bone cell undergoes its ownmechanotransduction through a series of bio-chemical cascades whereas a whole multicellularsystem such as the osteocyte-cannaliculi syncy-tium can function as a connected cellular net-work utilizing the summation of the biochemicalattributes of many cells. The bioelectric theoryconcedes just this, in that each small contributionfrom the simple flow of fluid after deformationcan actually lead to an enormous change throughbiochemical amplification. This is the tissue levelmechanism thought to be responsible for grossanatomical alteration in alveolar bone shapeand dimension. The self-regulatory (second or-der) cybernetic mechanism is called a mech-anostat, a concept developed by the Frost andJee collaboration. This is a biological machinethat determines whole-bone strength and formsa tissue-level negative feedback system. Twothresholds define a range of bone strains thatdetermine the organs form and function byswitching on and off the necessary biologic

mechanisms that increase or decrease its localphysiologic activity.20,22

Moss FMH, Singhs SMH, and the Utah Par-adigm in synthesis allow us a fully integratedintellectual infrastructure within which molecu-lar or ionic triggering of intrinsic or genomicfactors, which ultimately lead the system to ex-press the necessary biological tools for bone re-modeling, can be organized. With orthodonticforces as the extrinsic or epigenetic factor, asseen in Baumrinds model, the skeletal compo-nents are manipulated to allow the movement of

teeth through this functional matrix of bone,tissue, and fluid, and redefining it structurallyand functionally.

Specific Molecular Mechanisms

Transcription factor (TF) biology is a key com-ponent of the molecular response to orthodon-tic force. TFs are specialized proteins formed inthe cytoplasm that migrate into the nucleus and



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attach to very short nucleotide segments ofDNA. This binding of TFs either promotes geneexpression or suppression. The overall processby which molecules transmit mechanical forceinto bone cell genomes is the forementioned

signal transduction (Figs 1, 2). We may ask how bone cells sense the pres-

ence of mechanical load. This is done throughphysical distortion of the force-affected cells.This cell deformation triggers a whole complexof molecular events or biochemical cascade(pathways) exemplified in Fig 2. It is importantto bear in mind that orthodontic force directedinto the PDL and adjacent alveolar bone causesstructural alterations in tensegrity (tensional in-tegrity) of the cytoskeleton and nucleus; (see:http://www.childrenshospital.org/research/ingber) and functional changes in the extracel-lular matrix, the cell membrane and the nuclearmatrix proteins. This is immediately followed bynucleotide activation by single or multiple TFsand subsequent gene suppression or expression

ultimately affecting ribosomal activity (transla-tion; Fig 3).

Investigations into the relationship betweenbone stress and cellular responses have beenperformed for some time, but the exact path-

ways remain unclearly defined. Pavalko and coworkers discuss an interesting concept termedthe mechanosome, which is conjectured tofunction as an intermediate biochemical path-way.23 A proposed genomic communication sig-nal, the mechanosome may mediate externalmechanical stimuli from the extracellular matrixto influence architectural transcription factorsin the nucleus. While very little experimentaldata have explicated the exact nature of a mech-anosome, it serves as an interesting working hy-pothesis23 (Figs 4, 5). In the words of Pavalko

and coworkers23

:

We propose that mechanical information is relayed from the

bone to the gene in part by a succession of deformations,

changes in conformations, and translocations. The load-

Figure 1. Intracytoplasmic schematic of bone cell showing nuclear envelop on the left. Various cytoplasmic proteinsare evident, with a helical protein touching the nuclear envelope as part of signaling. Signal transduction from cellmembrane via second messengers to nuclear pores. The mechanosome is conjectured to work with second messen-gers activated by external mechanical stimuli from the extracellular matrix taking in data to architectural transcriptionfactors. Many molecular biologists emphasize the importance of studying morphogenesis as a transcriptional event sotissue engineering may be based on pharmaceutical aids. (Source: http://www.temple.edu/stl/ . The Signal Trans-duction Lab, as envisioned by Audre Geras. Reprinted with permission. 2008 Audra Geras, Geras HealthcareProductions. www.audrageras.com) (Color version of figure is available online.)

http://www.childrenshospital.org/research/ingberhttp://www.childrenshospital.org/research/ingberhttp://www.temple.edu/stl/http://www.temple.edu/stl/http://www.temple.edu/stl/http://www.audrageras.com/http://www.audrageras.com/http://www.audrageras.com/http://www.audrageras.com/http://www.temple.edu/stl/http://www.childrenshospital.org/research/ingberhttp://www.childrenshospital.org/research/ingber


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induced deformation of bone is converted into the deforma-

tion of the sensor cell membrane. This, in turn, drives

conformational changes in membrane proteins of which some

are linked to a solid-state signaling scaffold that releases

protein complexes capable of carrying mechanical informa-

tion, mechanosomes, into the nucleus. These mechano-

somes translate this information into changes in the geometry

of target gene DNA, altering gene activity; bending bone

ultimately bends genes.

While there is dispute about the exact natureof these mechanisms it would seem that Ingberswork intimates what Pavalko has stated, indeedbending bone ultimately bends genes.23,24

Recent studies have investigated the molecu-lar mechanisms of PDL cells regulating the boneremodeling process. When compressive force isnot present, PDL cells secrete osteoprotegerin

Figure 2. The image demonstrates most graphically, with the well-investigated NF-B pathway, the complexity ofthe molecular biology of signal transduction at the cellular level. It is conjectured that orthodontic anddentofacial orthopedic forces evoke similar complicated biochemistry, yet the burgeoning knowledge of thismolecular biology opens a new frontier for pharmaceutically facilitated OTM. (Source: Copyright 2006ProteinLounge.com Reprinted with permission.) (http://www.medscape.com/viewarticle/479893_2. Reprinted

with permission.) (Color version of figure is available online.)

http://www.medscape.com/viewarticle/479893_2http://www.medscape.com/viewarticle/479893_2http://www.medscape.com/viewarticle/479893_2http://www.medscape.com/viewarticle/479893_2


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(OPG) to inhibit the differentiation of the oste-oclasts.25 Secretion of OPG by PDL cells pre- vents resorption of alveolar bone and subse-quent disruption of the PDL. This osteoclasticinhibitory mechanism maintains the teeth in thealveolar socket in the physiologic but dynamicsteady state. Tooth eruption is the only period oftime when the secretion of OPG by dental folli-

cle (precursor of PDL cells) is not present be-cause osteoclast formation and activation arenecessary to form an eruption pathway.26

Orthodontic treatment, however, changesthis secretion process. Compressive force trig-gers the secretion of another factor, called theligand receptor activator of NF-B (RANKL)from PDL cells (Fig 2). RANKL is an importantregulator of osteoclast differentiation and activ-ity. Upregulation of RANKL induces osteoclasto-

genesis resulting in alveolar bone resorption andsubsequent OTM. Increased RANKL expressionin compressed PDL cells was also observed inpatients with severe external apical root resorp-tion induced by orthodontic treatment.27 Thisresorption was mainly caused by upregulatedosteoclastogenesis. The RANKL-OPG ratio canbe used as a potential diagnostic assay and as the

determinant factor for root resorption.PDL cells, therefore, influence osteoclastdifferentiation through RANKL stimulationand OPG inhibition. Orthodontic compressiveforce significantly increased the release ofRANKL and decreased that of OPG in humanPDL cells in a time- and force magnitude-dependent manner in gingival crevicular fluid(GCF).28 Such increase of RANKL levels wasapproximately 16.7-fold, and the decrease of

Figure 3. Stimulus at the cell membrane, for example, cell deformation, triggers a whole complex of molecularevents or biochemical cascade exemplified in Fig 2, immediately followed by nucleotide activation by single ormultiple transcription factors and subsequent gene suppression or expression ultimately affecting ribosomalactivity (translation). (Source: http://stemcells.nih.gov/info/scireport/appendixA.asp. Reprinted with permis-sion.2001 Terese Winslow www.teresewinslow.com) (Color version of figure is available online.)

http://stemcells.nih.gov/info/scireport/appendixA.asphttp://stemcells.nih.gov/info/scireport/appendixA.asphttp://www.teresewinslow.com/http://www.teresewinslow.com/http://www.teresewinslow.com/http://stemcells.nih.gov/info/scireport/appendixA.asp


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OPG was 2.9-fold, as compared to the control.Local transfer of OPG gene to periodontiumneutralized the RANKL-mediated osteoclasto-genesis induced by compressive force and inhib-ited OTM.29

Clinical SignificanceBone Response

The understanding of biochemical mechanismsof OTM allows the orthodontist to control thenature of tooth movement so physiologic varia-tion does not become pathologic. Reciprocaloscillating force on a tooth constitutes the jig-gling movement associated with the occlusaltrauma and accelerated irreversible bone loss in

periodontitis.30 Indeed, reciprocating trauma,moving a tooth in and out of a prematurityunder parafunction, may even alter the qualita-tive nature of the subjacent bacterial flora creat-ing a pathological bacterial biofilm (dentalplaque) dynamic clinically undetectable by thebusy orthodontist.31

However, OTM, dangerously characterized asa kind of controlled version of occlusaltrauma, differs from irreversible trauma in thatOTM produces a net displacement of the toothin space. The difference that distinguishes dis-ease from therapy, where similar physiologicprocesses are at work, is the ability to control theclinical outcome. This is why the biologic ap-proach to orthodontic care and an intellectual

Figure 4. Schematic illustrating pathways associated with the mechanosome hypothesis presently under inves-

tigation. Note interplay between biochemical factors and the structural tensional integrity (tensegrity) of thecytoskeleton, ably studied by Professor Ingber. (Source: Pavalko FM, Norvell SM, Burr DB, Turner CH, DuncanRL, Bidwell JP: A model for mechanotransduction in bone cells: the load-bearing mechanosomes. J Cell Biochem88:104-112, 2003. Reprinted with permission of John Wiley & Sons, Inc.) (Color version of figure is availableonline.)



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appreciation of periodontal pathophysiology, al-veolar bone dynamics, and biologic engineeringof the surrounding bone tissue is so critical tosuccessful therapy. When physiologic force canbe modulated to benefit and protect the patientfrom therapeutic excess, the orthodontist ormore specifically the dentofacial orthopedist, isacting as kind of applied biological scientistand not merely a technically proficient artisanwho can move clinical crowns.

This is true not merely for adult patients.Capelli and coworkers published compellingepidemiological and microbiological data sug-gesting that frank attachment loss may bedemonstrated in significant adolescent co-horts.32 Without some biological awareness, theclinical artisan, focusing on mechanistic art, may jeopardize the patients long-term periodontalhealth since an increase in postdebonding tissuetonus mimics but hides subjacent periodontal

attachment loss and self-perpetuating disease be-yond the reach of oral hygiene aids even whenused assiduously.

The Pharmacological Dimension

In the future, pharmacologic products may beused in regulating the rate of orthodontic toothmovement. They may work by regulating the cyto-kines, growth factors, or systemic factors involved

in bone remodeling. Drugs that can influence therate of tooth movement can be characterized intofive main categories: hormones, bisphosphonates,vitamin D metabolites, fluoride, and nonsteroidalanti-inflammatory drugs (NSAIDs).33

Systemic hormones such as estrogen, androgen,and calcitonin cause an increase in bone mineralcontent, bone mass, and a decrease in the rate ofbone resorption. As a result, they could delayOTM. On the other hand, thyroid hormones and

Figure 5. The load-bearing mechanosome explains mechanotransduction in bone cells in general, yet the exactrole in surgical or nonsurgical dentofacial orthopedics awaits further research. The reader is encouraged tofurther investigate this promising new frontier in the molecular biology of the orthodontic specialty. (Source:Pavalko FM, Norvell SM, Burr DB, Turner CH, Duncan RL, Bidwell JP: A model for mechanotransduction inbone cells: the load-bearing mechanosomes. J Cell Biochem 88:104-112, 2003. Reprinted with permission of

John Wiley & Sons, Inc.)



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corticosteroids increase osteoclast bone resorptionand inhibit osteoblastic function, respectively,which might increase the rate of OTM contribut-ing to a less stable orthodontic result.

Drugs such as bisphosphonates, vitamin D me-

tabolites, and fluorides can delay OTM. Bisphos-phonates, contemporarily popular in our society,are potent blockers of bone resorption. They in-hibit osteoclastic metabolism and decrease num-bers of osteoclasts. Vitamin D3 regulates the phys-iologic amount of calcium and phosphorus.Research shows that vitamin D3 also increasesbone mass and reduces fractures in osteoporoticpatients.34 Fluoride stimulates the growth and syn-thetic activity of osteoblasts and bone formation.In the form of sodium fluoride, it inhibits theosteoclastic activity and reduces the number ofactive osteoclasts.

Nonsteroidal anti-inflammatory drugs (NSAIDs),commonly employed analgesics in daily dentaltreatment, also have been shown to reduce boneresorption and delay the bone response to respec-tive tooth-borne pressure. They inhibit cyclooxy-genase enzyme involved in prostaglandin synthe-sis. Aspirin and other acetylsalicyclic acids (ASAs),such as ibuprofen, are able to slow down orth-odontic tooth movement as may indomethacin-related agents.35

Locally applied statins may also have somefuture relevance to alveolus engineering be-

cause they are capable of inducing both angio-genesis and regional osteogenesis necessary forregeneration. Statin, a coenzyme A reductaseinhibitor, increases BMP-2 gene expression forbone formation by blocking the mevalonatepathway in cholesterol production. In an in vivostudy, the amount of new bone formed by statinmixed with a collagen carrier was quantitativelyassessed and results showed that 308% more newbone was formed in defects grafted with statin thanthose grafted with the carrier alone. Immunolocal-ization studies on the early healing of the defects

grafted with statin showed vascular endothelialgrowth factor (VEGF), BMP-2, Cbfa-1 expression,and new bone formation occurred 1 day earlierthan those grafted with the carrier alone.36

Prostaglandins and leukotrienes have the po-tential to enhance tooth movement and are focifor clinical investigations. They stimulate boneresorption by increasing the number of oste-oclasts and activating existing osteoclasts. Theinjection of prostaglandin has been shown to

accelerate OTM in both animals and humans.Oral administration of misoprostol, a prosta-glandin E1 analog, has been shown to enhanceOTM with minimal root resorption.37 Adminis-tration of prostacyclin (PGI2) and thromboxane

A2 (TxA2) analogs in rats have been shown toincrease the number of osteoclasts, osteoclasticbone resorption, and rate of OTM.38 Therefore,while some pharmaceutical agents hold promiseof enhanced bone remodeling, long-term admin-istration of NSAIDs or ASAs should be avoidedduring orthodontic therapy.

Cytokines OPG and RANKL could becomethe next targets of pharmaceutical approachin controlling tooth movement. As previouslydescribed, OPG released by PDL cells inhibitsthe differentiation of osteoclasts and preventsbone resorption. RANKL, however, induces oste-oclastogenesis resulting in alveolar bone resorp-tion. In fact, Keles and coworkers recently de-signed a constant orthodontic force model anddemonstrated that tooth movement is reducedwhen OPG is systemically administrated in mice.39

Biological modulators could be administrated lo-cally to control undesired tooth movement at an-chor units or systemically to enhance post treat-ment stability.

Twenty-first Century Research and

Clinical ProtocolsGenetic Tests

Proinflammatory cytokines play an important rolein periodontal diseases. Interleukin-1 (IL-1), inparticular, has been well demonstrated in bonedestruction commonly seen in adult periodonti-tis.10 IL-1 is increased in inflamed gingival tis-sue and GCF in patients with periodontitis.40

Treatment with scaling and root planing de-creases IL-1 levels in the GCF.41

The IL-1 gene cluster on human chromo-

some 2q13 contains 3 genes. Two genes (IL-1and IL-1) encode proinflammatory cytokineproteins IL-1 and IL-1, respectively. The thirdgene (IL-1RN) encodes a related protein (IL-1ra) that acts as a receptor antagonist.42 Recentresearch has improved public knowledge on therole of the proinflammatory cytokine in OTM.Both IL-1 and tumor necrosis factor- (TNF-)have been implicated in osteoclastic bone re-sorption accompanying OTM. Studies from Al-



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hashimi and coworkers43 have shown the in-creased levels of IL-1 in vivo mRNA expressionduring orthodontic treatment. And such in-creased levels of IL-1 are measurable in GCFand gingival tissues of patients.40

Research has shown that such increasedIL-1 expression is associated with the poly-morphisms of IL-1 gene clusters. IL-1 genehas 2 alleles at the 3954 position. Allele 1 ofthe IL-1 gene results in low production ofIL-1. On the other hand, allele 2 is associated with adult periodontitis. A change in IL-1allele to allele 2 at3954 position can resultin a 4-fold increase in IL-1 production lead-ing to bone destruction in adult periodonti-tis.44 Kornman and coworkers10 reported thatpatients who were nonsmokers and positive forallele 2 at IL1 899 and IL1 3954 loci hada 6.8 times greater chance of having severeperiodontitis than those who did not possessthese alleles. IL-1 genotype can thus be astrong predictor of susceptibility to severe pe-riodontitis in adults.

Research has demonstrated that IL-1 genepolymorphism at the 3954 position can alsopredispose patients to external apical root re-sorption (EARR), in which dental hard tissuesare attacked by osteoclasts. Individuals homozy-gous for the IL-1 allele 1 have a 5.6-fold in-creased risk of EARR greater than 2 mm, as

compared with heterozygocity for the IL-1 al-lele 1. The diallelic variation of IL-1 gene be-tween individuals results in different expressionlevels of IL-1, leading to various physiologicalresponses of apical roots to orthodontic forces.Decreased IL-1 expression in individuals ho-mozygous for the IL-1 allele 1 may result inrelatively less catabolic bone resorption at thecortical bone interface with the PDL, which inturn may traumatize the root of the tooth, trig-gering a cascade of fatigue-related events lead-ing to root resorption.45 Recent studies by Jager

and coworkers in rats have shown that inhibitionof cytokine activity by soluble receptors to IL-1and TNF- reduces the number of osteoclasts onthe bone surface and inhibits OTM.46 Althoughsuch application of soluble receptors does notseem to be a specific treatment regimen forpreventing root resorption in the course ofOTM, there is progress toward prediction ofunwanted side effects in creation of adjunctivepharmaceutical therapy.

The findings of genetic components such asIL-1 involved in periodontitis and OTM willallow orthodontists to employ genetic suscep-tibility testing for possible complications be-fore orthodontic treatment when the clinical

process is rendered more practical and con-ceptually more refined. Presently a reliableand practical market to patient sampling is inthe development stage. GCF or buccal muco-sal epithelial cells can be collected and as-sessed for IL-1 genetic polymorphisms. Inthis way, orthodontists can screen patients forDNA markers suggesting susceptibility to peri-odontitis or EARR. Orthodontists can thenbetter inform patients of periodontal andorthodontic risks. Currently, a genetic suscep-tibility test is available for severe chronic peri-odontitis based on the study by Greensteinand colleagues.47 In the future, similar genetictests could be developed to assess the risk ofEARR or even manipulate sufficient limitedinflammatory events to facilitate movement orenhance stability. Such tests offer an intrigu-ing tool for biologic orthodontists and dento-facial orthopedists to develop a thorough bio-logically based diagnosis and treatment plan.

Conclusion

Recently, developments in clinical practice have

incorporated OTM as a sophisticated therapeu-tic adjunct in dental arch development, boneregeneration, and preprosthetic periodontaltherapy. The relationships between orthodon-tics and periodontology are closer than ever andcomplicated also by the popular incorporationof dental implants and temporary anchoragedevices (TADs). These evolutionary develop-ments in the orthodontic specialty suggest thepresence of equally sophisticated biologicalevents within the PDL and alveolar bone dur-ing OTM.

In the past, scholars have proposed severaltheories regarding bone remodeling duringOTM, which in light of modern cell biology canbe viewed as overly simplistic and unproductiveby contemporary societal needs and 21st centurypatient expectations of applied biological sci-ence. Contemporary models include Baum-rinds viscoelastic13 and Johnsons fluid flow the-ories,12 which may help link clinical practice with pharmacologic and tissue engineering, a



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nascent science already being developed inother fields of clinical care. Recent discoveries ofthe interplay between RANKL and OPG mole-cules in regulating bone remodeling demon-strate the potential of molecular biology in wid-

ening the clinical horizon of dentofacialorthopedics. It is possible that a combination ofall the theories can be synthesized under thetheories proposed by Moss, Singh, Frost, and Jeeand the intrepid research of Drs. Wilcko andFerguson.9

The biochemical mechanisms of OTM mimicon a smaller scale some inflammatory events thatoccur during occlusal trauma and the acceler-ated bone loss in periodontitis. Consequently,clinicians who ensure that concomitant peri-odontal care accompany their mechano-thera-peutic protocol can minimize the likelihood ofpermanent damage to the periodontal tissuesapparently initiated by deceptively benign gin-gival hyperplasia. Thus, caution, informed con-sent, and prudent concern are always wise prac-tices. With understanding of histobiochemicalmechanisms underlying OTM, future dentofa-cial orthopedics involving pharmacologicaltreatment may be as common as interarch elas-tics are now. Certainly, growing bone, a com-mon practice in distraction osteogenesis and re-generation, is quite possible in the alveolus, andmay promise some relief from the timid reliance

clinicians place on patient cooperation and ex-traction protocols. We hope that other col-leagues will share our trust and eager interest inthese applications of modern life science in ourspecialty, so that investigation of various drugsand hormones to enhance orthodontic move-ment may someday lead to their use as pharma-cological modifiers of OTM.

Our view is that future orthodontic specialiststraining should and will, by the natural evolutionof scientific pedagogical imperatives, eventuallysupplement but not replace conventional orth-

odontic mechanotherapy and integrate it with thesciences of clinical pharmacology, periodontics,cellular genetics, and molecular biology. The ques-tion remains whether we shall do it as a reflex toregulation, as homage to earlier scholars, or simplyto provide optimal patient care. The integration ofcontemporary science and clinical orthodontics isa professional imperative, lest our future be de-fined by others less qualified, be they bureaucraticusurpers or crass retail marketers.

Acknowledgments

We greatly appreciate the invaluable insights and sugges-tions from Dr. Neal C. Murphy, Lecturer at the Departmentof Orthodontics at UCLA School of Dentistry, AssociateProfessor in Orthodontics at Case Western University. Dr.Murphy is a great teacher. Carpe Diem! We wish to acknowl-

edge Shelby Padua, UCLA School of Dentistry, for proof-reading and contributing to this study. Thanks also to Dr.Chin-Yu Lin, Director of Orthodontics at Harvard School ofDental Medicine, for giving insights and providing refer-ences on the molecular basis of OTM. Thanks also to theadvice tendered by Dr. A. Lala, Lecturer at Harvard Schoolof Dental Medicine. Special appreciation is extended toJoseph P. Bidwell, PhD, whose development of the mech-anosome model, in collaboration with colleagues at IndianaUniversity-Purdue University at Indianapolis consortium ofclinicians and scientists, helped stimulate interest in thefascinating molecular genetic biology that underlies the sci-ence and art of the orthodontic specialty.

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