Research in Tooth Movement Biology: The Current Status

Vinod Krishnan, Sajan V. Nair, Ambili Ranjith, and Zeev Davidovitch

The increased focus on the biological basis of orthodontics is expanding our knowledge and is augmenting our understanding of the clinical effects of mechanical forces on living tissues. This has led to the evolution of a well-dened technique-oriented profession into a comprehensive specialty, incorporating facets of all elds of medicine, emphasizing that live human beings are being treated, not dental typodonts. Research in the eld of orthodontic tooth movement comprised a signicant share among articles published in all orthodontic peer-reviewed journals in the past decade. This article provides an organized scheme for tooth movement research studies conducted during the past 5 years, divided into areas such as marker studies, root resorption, accelerating or decelerating tooth movement, and the expression of various molecules and cells in the process of mechanical force-induced tissue remodeling. (Semin Orthod 2012;18:308-316.) 2012 Elsevier Inc. All rights reserved.

esearch in the eld of orthodontic tooth movement has evolved rapidly in the past decade, as evidenced by the plethora of manuscripts published in various international peerreviewed journals. The fact that judicious application of mechanical force can generate optimal reactions by paradental tissues, at the cellular and molecular level, is being documented in current research ndings. The importance of each and every tissue, be it alveolar bone, periodontal ligament (PDL), root cementum, and associated vascular and neural networks, has been investigated, and the role played by each

Professor and Head, Department of Orthodontics, Sri Sankara Dental College, Trivandrum, Kerala, India. Senior Lecturer, Department of Orthodontics, Sri Sankara Dental College, Trivandrum, Kerala, India. Reader, Department of Periodontics, PMS College of Dental Sciences and Research, Trivandrum, Kerala, India. Clinical Professor, Department of Orthodontics, School of Dental Medicine, Case Western Reserve University, Cleveland, OH; and Chairman Emeritus, Department of Orthodontics, Harvard University School of Dental Medicine, Boston, MA. Address correspondence to Vinod Krishnan, BDS, MDS, MOrth RCS ED, PhD, Department of Orthodontics, Sri Sankara Dental College, Trivandrum, Kerala 659043, India. E-mail: vikrishnan@yahoo. com 2012 Elsevier Inc. All rights reserved. 1073-8746/12/1804-0$30.00/0 http://dx.doi.org/10.1053/j.sodo.2012.06.009

has been delineated.1 This growing attention to the biological basis of orthodontics expands current knowledge and augments understanding of the effects of mechanical forces on living tissues in the clinical setting. Due to these developments, orthodontics, which for a long time has been viewed as a traditional, established, and well-dened technique-oriented profession, has steadily evolved into a comprehensive specialty, incorporating facets of all elds of medicine, emphasizing that live human beings are being treated, and not dental typodonts. A search in the PubMed database with the key words orthodontic tooth movement retrieved 5358 articles, and when the search was narrowed down to tooth movement and orthodontic forces, the number of articles was reduced to 672. Most of the articles in this search result were published in the year 2009, followed by 2011, indicating the signicantly increased interest in this particular area for the past 3-4 years. This manuscript provides an organized scheme for tooth movement research studies, divided into areas such as marker studies, root resorption, accelerating or decelerating tooth movement, and the expression of various molecules and cells in the process of mechanical forceinduced tissue remodeling. The article focuses

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on research performed in the eld of tooth movement for the past 5 years (2006-2011), to provide readers with information about recent research and future research directions.

Marker Studies Gingival Crevicular Fluid and Orthodontic Mechanotherapeutics

Gingival crevicular uid (GCF), a transudate from interstitial tissues produced by an osmotic gradient, consists of a complex mixture of serum, cells, oral bacteria, and many mediators and enzymes of gingival inammation.2-4 Orthodontic tooth movementinduced tissue remodeling is triggered by a sterile inammatory process, which increases the vascular permeability as well as the amount of GCF production.5,6 Iwasaki and Nickel,6 in a review published in 2009, provided a detailed list of all markers in the GCF, and categorized them as metabolic products of paradental remodeling, inammatory mediators, enzymes, and enzyme inhibitors. Increased or elevated levels of prostaglandin E2 and interleukin (IL)-1 after mechanical force application were initially described by Saito et al7 and Grieve et al.8 Subsequently, there has been a myriad of publications describing the elevated status of biomolecules in GCF, with mechanical force application through orthodontic appliances. Recently, Chibebe et al9 discovered increased levels of prostaglandin E2 in juveniles, compared with adults, and correlated this nding with the speed of tooth movement. According to Chibebe et al,9 the absence of smoking and periodontal disease in juveniles, along with increased levels of sex hormones, resulted in an earlier and faster inammatory response to local changes, leading to a more rapid pace of tooth movement. In contrast with juveniles, in adults, with increasing age, there is a decrease in the proliferation of PDL cells, organic matrix production, as well as the relative amount of soluble collagen and alkaline phosphatase activity. Cellular differentiation is also affected with the aging process, as well as periodontal disease and smoking habits, resulting in a decreased number of osteoblasts and osteoblast-precursor cells.9-11 Enzymes such as matrix metalloproteinases (MMPs) and leptin have received close attention in the past, as has the role of chemoattractant

cytokines. Recently, Capelli et al12 examined the GCF levels of MMP-3, MMP-9, MMP-13, and of the chemokines macrophage inammatory protein (MIP)-1 , monocyte chemoattractant protein (MCP)-1, and RANTES (Regulated on Activation Normal T Cell Expressed and Secreted) at different time points during orthodontic tooth movement. Capelli et al12 observed a statistically signicant elevation for MMP-3, MMP-9, and MMP-13 on the compression side of tooth movement after 1 hour of force application, but found it decreasing sharply over the next 24 hours. They attributed this nding to an immediate consumption of enzymes related to the degradation of collagen. From 24 hours to 80 days, they observed a progressive increase in MMP levels. The ndings of Alfaqeeh and Anil13 conrmed this progressive increase in collagen degradation with orthodontic force application. Alfaqeeh and Anil13 documented an elevation in levels of N-telopeptide, a type I collagen degradation product, incident to application of orthodontic forces. Surprisingly, the levels of MCP-1, MIP-1 , and RANTES in GCF did not seem to be altered by orthodontic force application,12 which was contradictory to the previous nding that chemokines are upregulated with orthodontic force application.14 Although the orthodontic literature contains numerous reports on increased elevation of biomarkers in the GCF after the application of orthodontic forces, the difculty in sample collection, its quantication and localization of molecules, interpretation of data, and, more importantly, its use in a clinical setting, as well as clinical validity of the results, remain questionable. Drummond et al,4 through a longitudinal randomized split-mouth study, conrmed that the GCF volume, measured with the help of a Periotron 8000 (Oraow, Inc., Smithtown, NY), after sample collection and comparing with test tooth as well as control tooth at baseline (immediately before the mounting of the orthodontic appliance) and after 1 hour, 24 hours, and 7, 14, and 21 days, cannot be taken as a reliable marker for orthodontic tooth movement, as GCF volume is determined by subclinical inammation. The results, that GCF volume is not a reliable marker, suggest that a new, noninvasive, and more reliable procedure needs to be developed for analyzing and evaluating orthodontic tooth movement, which will facilitate the stan-

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dardization of the collection, analysis, and clinical utilization as a powerful diagnostic tool.

Salivary Biomarkers and Bone Remodeling

The trend toward the use of body uids other than blood, such as urine and cerebrospinal uid, to aid in the diagnosis of diseases has been replicated in orthodontics by incorporating saliva as a major diagnostic tool in recent years. The serum components of saliva, which are derived primarily from the local vasculature, originating from the carotid arteries, have resulted in saliva being a prodigious uid source of many molecules found in the systemic circulation, making it a potentially valuable aid in the diagnosis of various systemic diseases.15 Because of the rapid, noninvasive, and easy methods of acquiring saliva, which require less manpower and materials than for GCF, it is frequently being used for diagnosis of periodontal disease. Moreover, it represents a pooled sample from all periodontal sites, in contrast to GCF. Whole saliva clearly provides an overall assessment of a particular disease or risk status at the subject level, instead of site- or tooth-level assessment in GCF.16 With current advancements in this eld of research, the elevation of or decrease in all hostderived biomarkers, such as cytokines, chemokines, enzymes, and immunoglobulins, which were previously identied from GCF, can be identied through salivary diagnostics. Periodontal research has used salivas potential to identify all the biomarkers, such as inammatory mediators ( -glucuronidase, C-reactive protein, IL-1 , IL-6, tumor necrosis factor- , and MIP1 ), molecules of connective tissue destruction ( 2-macroglobulin, MMPs, tissue inhibitors of MMPs, aminotransferases, cathepsin, and elastase), and bone remodeling biomarkers (alkaline phosphatase, C-terminal cross-linking telopeptide of type I collagen, pyridinoline crosslinked carboxyterminal telopeptide domains of type I collagen, receptor activator of NF- B ligand [RANKL], osteoprotegerin [OPG], hepatocyte growth factors, osteocalcin, and osteonectin), for diagnosis of various stages of disease processes.16 For more information on how saliva can be used for diagnosis of various systemic and local diseases, the readers are referred to the

excellent textbook by Wong, published in 2008.17 Although the periodontal literature is replete with articles on salivary biomarker expression patterns in periodontitis patients, orthodontic publications on this subject are limited in number. Only 2 studies were found in which it was reported that the expression of total proteins is not altered by mechanical force applied to teeth.18,19 However, Hussian and Ghaib18 reported a statistically signicant decrease in the mean total protein concentration in male subjects and an insignicant increase in the mean total protein concentration in female subjects while evaluating molecular weight of salivary proteins measured with sodium dodecyl sulfate polyacrylamide gel electrophoresis in unstimulated whole saliva from 50 patients under orthodontic treatment. Burke et al19 demonstrated a signicant difference in cyclic adenosine monophosphate-dependent protein kinase subunit (RII) after orthodontic separator placement, indicating that the cyclic adenosine monophosphate pathway is activated after tooth movement is initiated. It is surprising to see that orthodontic researchers have not used the full potential of this body uid, saliva, for assessment of progressive tooth movement with mechanical force application.

Markers for Root Resorption

Root resorption is sometimes an unwanted iatrogenic outcome of orthodontic tooth movement. Root resorption has been linked to faulty biomechanics and cases where dental roots are moved excessively or unnecessarily. Research in this area suggests several risk factors are associated with root resorption, including preexisting root conditions, type of tooth movement, amount and type of force, and treatment duration.20,21 There also exists a racial predilection in its occurrence, with Asians showing fewer predilections than whites and Hispanics.5,22,23 During the process of root resorption, organic matrix proteins and cytokines are released into the nearby crevices, and there seems to be a difference between levels of these proteins in the GCF of subjects undergoing orthodontic treatment and with radiographic signs of root resorption and in those subjects not in treatment and without radiographic signs of root shortening. Also,

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differences exist between levels of these proteins, such as dentin matrix proteins (DMPs) and dentin sialoproteins (DSPs), in GCF of subjects with mild and severe root resorption, evaluated by radiographs.20 Candidate genes associated with external apical root resorption have been identied, and the list includes IL-1 , OPG, RANKL, and osteocalcin, to name a few. It is likely that differential expression of these molecules that govern osteoclast/odontoclast function plays a role in determining individual susceptibility to the root resorption process, and this might be the reason why certain individuals may react with exaggerated response.24 The importance of biochemical assays in the early detection of the root resorption process was initially demonstrated by Mah and Prasad,25 who showed elevated levels of dentin phosphoproteins in the GCF. Moreover, Balducci et al26 reported nding elevated levels of DMP1, DSP, and dentin phosphophoryn in the GCF of patients undergoing orthodontic treatment, in whom there were radiographic signs of root resorption. Because the concentrations of these molecules in the study groups were signicantly higher than those of the control group, the investigators suggested that these proteins could be potential markers for root resorption. The ndings reported by Mah and Prasad25 were recently conrmed by Zuo et al27 in a study on 36 Wistar rats, further emphasizing the validity of DMP1, DSP, and phosphophoryn as markers of root resorption during orthodontic treatment. George and Evans20 demonstrated the presence of bone matrix proteins, such as osteopontin, cytokines, OPG, and RANKL in subjects showing evidence of root resorption. This relationship of the RANK/RANKL/OPG system with the root resorption process was further conrmed by Tyrovola et al,28 who had found positive correlations between the blood serum RANKL concentrations and the degree of root resorption after orthodontic treatment, whereas blood serum OPG levels declined. These results suggest that the initial blood serum concentrations of RANKL/OPG may be used as a predictor for root resorption incident to orthodontic treatment. Tyrovola et al28 were the rst to report on differential levels of RANKL/OPG in the blood serum of rats with severe orthodontic root resorption.

Asano et al29 linked the role of the chemokines IL-8, cytokine-induced neutrophil chemoattractant-1, and MCP-1/CCL2 to root resorption during orthodontic tooth movement. The detection of immunoreactivity for cytokineinduced neutrophil chemoattractant-1/CXCR2 and MCP-1 in odontoclasts and PDL broblasts in rats after an orthodontic force of 50 g on day 7 was suggestive of the involvement of these molecules in root resorption. Extending research to the role of antidentine antibodies and the role of autoimmune mechanisms in root resorption, de Paula Ramos et al30 analyzed serum immunoglobulin G levels and salivary secretory immunoglobulin A (sIgA) levels. They used human dentine extract as antigen and showed increased sIgA levels in saliva at the beginning of therapy in patients who later showed moderate to severe resorption after 6 months of treatment. de Paula Ramos et al30 conrmed that in humans, the presence of an abnormal root shape and initial levels of anti human dentine extract sIgA in saliva are associated with the degree of upper central incisor root resorption. The aforementioned discussion suggests that dentin degradation products, bone remodeling products, cytokines, chemokines, and immunoglobulins, all indicating progressive root resorption in patients, can be found in bodily uids, such as blood, GCF, or salivary samples, and that their uctuations may reect an association with the degree of orthodontic root resorption.31 However, these ndings have not yet resulted in widespread use of assays to measure these markers in the orthodontic clinic. Further research is required before the establishment of routine tests for the detection of specic biological markers of orthodontic root resorption. The avoidance, or minimization, of root resorption may be enhanced by applying appropriate biomechanics in orthodontic tooth movement.

Altering the Pace and Clinical Electrophysiology of Tooth Movement

Orthodontic tooth movement depends on bone remodeling and PDL reorganization along with neoangiogenesis and excitation of peripheral nerve endings.1 The fundamental principle behind the efforts to enhance the velocity of tooth movement is the concept, emanating from laboratory experiments, that has demonstrated that

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cells and tissues in culture are capable of responding to 1 stimulus at the same time. The cellular response to simultaneous stimuli can be inhibitory, additive, or synergistic. In the case of mechanical forceinduced tooth movement, the assumption is that the addition of an agent known to stimulate bone cell activities will enhance the velocity of tooth movement. Consequently, attempts to shorten orthodontic treatment time has attracted increasing interest in recent years. In a related study, Davidovitch et al32 applied direct electrical current, noninvasively, to cat gingivae near maxillary canines while they were being moved for 7 or 14 days, and reported that the combined application of mechanical force and direct electrical current resulted in signicant acceleration of canine movement. In addition, an immunohistochemical examination of the tissues surrounding the canines revealed intense staining for cyclic nucleotides in gingival broblasts and alveolar bone periosteal surface cells near the cathode and anode (Fig 1). Enhanced bone resorption was observed near the anode (PDL compression site), whereas bone formation was pronounced near the cathode (PDL tension site). In a preliminary clinical trial in young adult patients, a similar enhancement of canine movement has been observed (Davidovitch et al, unpublished data). Recently, a noninvasive removable enzymatic microbattery, using glucose as a fuel, was developed to administer minute electric currents to the alveolar bone and oral soft-tissues, thus becoming a possible source of the electrical power required for accelerating the velocity of orthodontic tooth movement.33 Based on the ability of cells to respond to simultaneously applied stimulatory signals, attempts were made to accelerate the pace of tooth movement with specic molecules, especially those that had been found to be intimately involved in inammation and bone healing. One of the rst messengers in this regard were prostaglandins, the inammatory mediators known to be involved in tooth movement. Yamasaki et al34 demonstrated accelerated tooth movement with local application of prostaglandin E1, without any adverse effects on local tissues. This effect was studied further by the same researchers33 and others35-40 and was found to be effective in accelerating tooth movement. However, the approach was not successful clini-

cally in human subjects, as these injections were painful and the exaggerated inammatory response had the possibility of increasing the incidence of dental root resorption.38,41,42 Although reports on investigations of the effects of iontophoresis,43 local vibratory stimulation,44 and pulsed electromagnetic elds45 demonstrated successful results in accelerating tooth movement, these methods, likewise, failed to gain clinical acceptance because of, at least in part, their systemic effects, most commonly dry mouth. The current research trend revolves around administration of macrophage colony stimulating factor (M-CSF), an early osteoclast recruitment/differentiation factor, to accelerate tooth movement.46 Brooks et al46 demonstrated that low doses of M-CSF were successful in increasing the expression of M-CSF downstream genes and tartarate resistant acid phosphatase (TRAP) and increasing the rate of tooth movement, whereas higher doses failed to do so. Surgical approaches to accelerate tooth movement date back to 1966, when Byloff-Clar47 demonstrated, by use of his histologic studies, the advantages of corticotomy-assisted tooth movement. Tenenbaum, a Spanish orthodontist, in 1970, reported the technique in detail.48 Later, articles were published in the orthodontic and related literature, outlining the advantageous nature of surgery, as far as accelerating tooth movement is concerned.49-53 Recently, alveolar augmentation with bone grafting, named periodontally accelerated osteogenic orthodontics, has been propagated by Wilcko et al,54 which demonstrated promising acceleration of the tooth movement process. Readers are referred to the article by Murphy et al55 in this issue of Seminars in Orthodontics for a detailed review of the technique and its historical perspective. Iglesias-Linares et al56 compared corticotomy and induced RANKL overexpression and concluded that although the corticotomy group showed a greater initial tooth movement increase, it experienced a gradual decrease due to the decrease in RANKL levels and the lower TRAP cell counts. However, induction of RANKL overexpression increased tooth movement to 41.27% compared with the control group. The aforementioned reports strongly suggest that orthodontic treatment can be accelerated by a combined application of mechanical force

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Figure 1. (A) Constant direct current, 20 mA, noninvasively, to the gingival and oral mucosa labial to the left canine of a cat. The right canine (control) received the same electrodes but without electrical current. Both canines were moved distally by an 80-g tipping force. The right canine, which had been subjected only to mechanical force, moved distally a smaller distance than the left canine, which had been administered a combination of mechanical force and electrical current. Transverse section, 6-mm thick, of a 1-year-old female cats mandible, after a 7-day exposure to sham electrodes (B) and constant application of a 20-mA direct current to the gingival mucosa, noninvasively (C). Bone denotes alveolar bone. The bone surface lining cells near the anode are at and most stain lightly for cyclic adenosine monophosphate ( 640 in B), whereas the bone surface lining cells near the cathode are larger and more darkly stained for cyclic adenosine monophosphate ( 640 in C). (Color version of gure is available online.)

and another stimulatory agent, physical or chemical, to teeth that need to be moved. The research along this avenue is continuing, and the prize remains the discovery of a practical way to correct malocclusions in a short time, efciently, and without creating undesirable side effects. Current ongoing research on stem cell therapy is showing promising results, although

its incorporation into regular orthodontic practice is still in the nascent stages.

Alveolar Bone Density and Tooth Movement

The use of cone-beam computed tomography and microtomography in orthodontic research

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has provided great insights into alveolar bone density changes incident to tooth moving forces. With the help of 3-dimensional computer models generated out of cone-beam computed tomography images, Chang et al57 demonstrated maximum bone density reduction toward the side of tooth movement. Contradictory results with microtomography analysis were obtained by Zhuang et al,58 who found that the bone fraction increased signicantly after orthodontic force was applied for 2 weeks, and trabecular separation decreased signicantly with a higher orthodontic force (100 g). The results of Zhuang et al58 suggest that the microarchitecture of the alveolar trabecular bone becomes denser, so it can adapt to greater mechanical stresses. This nding was in concordance with previous ndings by Garat et al59 in periodontitis patients. Garat et al59 demonstrated that, after periodontal infection is controlled, orthodontic force application results in increased bone volume with improved quality. All these results indicate the still inconclusive data on how alveolar bone behaves in response to orthodontic force application.

tooth movement had no effect on relapse, but a signicant positive correlation was found between the amount of active tooth movement and both the rate and the total amount of relapse. However, a contradictory result was published recently by Kilic et al,63 who stated that there exists a close relationship between the amount of relapse and orthodontic force magnitude. They further reported that greater relapse occurred during the initial days after appliance removal and emphasized the importance of inserting retention devices immediately after the removal of orthodontic appliances. On reviewing the literature on orthodontic relapse, a signicant lack of research data was noted regarding this important issue. Moreover, the existing literature also reports controversial ndings, introducing much ambiguity regarding relapse. This paucity of information weakens the foundations of orthodontics and indicates the urgent need for a more structured research approach, in both animal models and humans, to provide clinicians with more evidence-based results.

Orthodontic Relapse
Orthodontic relapse, an area of most signicant orthodontic importance, although much less investigated, has been receiving attention recently. Maltha and Kuijpers-Jagtman60 reported that the histologic changes occurring during the immediate posttreatment period, where maximum relapse changes are observed, are identical to those observed when performing active orthodontic tooth movement, with creation of pressure and tension areas, but in a reverse direction. They concluded that the rate of collagen turnover in the PDL ligament and gingiva was very fast, ruling out its role in relapse tendencies. They suggested the role of other extracellular matrix proteins in producing orthodontic relapse. In their study on rat incisors, King et al61 concluded that tooth movement relapses at a rate of approximately 14 m (0.014 mm) per day after 16 days of orthodontic treatment. van Leeuwen et al62 investigated the role of retention in preventing orthodontic relapse in a model of adult beagle dogs. They concluded that the force magnitude applied during active

Conclusions
Basic researchers continue, at an increasing pace, to contribute to the advancement of clinical orthodontics. These researchers benet from the publication of the outcomes of wellplanned investigations in every eld of medicine. From these interactions, orthodontic researchers have selected areas that may be helpful in addressing clinical issues faced by the orthodontist on a daily basis. The biological uniqueness of each patient dictates the need for continuous acquisition of knowledge. The present focus is on areas, such as monitoring the reaction of patients to mechanical forces by searching for bone remodeling markers in the GCF, saliva, and blood serum. Attention is paid to the speed of tooth movement, and efforts are made to enhance it, by adding certain physical and chemical agents to the mechanical orthodontic force. Orthodontic researchers have had major accomplishments, but new challenges have arisen, requiring continuation of the investigative effort both in the research laboratory and the associated clinic.

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References
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