The Ortho-Perio Patient: Clinical Evidence & Therapeutic Guidelines
DEDICATION
To the memory of our fathers
Library of Congress Cataloging-in-Publication Data
Names: Eliades, Theodore, editor. | Katsaros, Christos, 1962- editor.
Title: The ortho-perio patient : clinical evidence & therapeutic guidelines / edited by Theodore Eliades, Christos Katsaros.
Description: Batavia, IL : Quintessence Publishing Co, Inc, [2018] | Includes bibliographical references and index.
Identifiers: LCCN 2018035730 | ISBN 9780867156799 (hardcover) | eISBN 9780867158458
Subjects: | MESH: Malocclusion--therapy | Periodontal Diseases--therapy | Evidence-Based Dentistry
Classification: LCC RK523 | NLM WU 440 | DDC 617.6/43--dc23
LC record available at https://lccn.loc.gov/2018035730
© 2019 Quintessence Publishing Co, Inc
Quintessence Publishing Co, Inc
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Preface
Contributors
SECTION I: FUNDAMENTALS OF ORAL PHYSIOLOGY
1Bone Biology and Response to Loading in Adult Orthodontic Patients
Dimitrios Konstantonis
2Microbial Colonization of Teeth and Orthodontic Appliances
Georgios N. Belibasakis • Anastasios Grigoriadis • Carlos Marcelo da Silva Figueredo
3Changes in the Oral Microbiota During Orthodontic Treatment
William Papaioannou • Margarita Makou
4Pellicle Organization and Plaque Accumulation on Biomaterials
George Eliades • Theodore Eliades
SECTION II: PERIODONTAL CONSIDERATIONS FOR THE ORTHODONTIC PATIENT
5Periodontal Examination of the Orthodontic Patient
Giovanni E. Salvi • Christoph A. Ramseier
U Etiology and Treatment of Gingival Recessions in Orthodontically
6Treated Patients
Raluca Cosgarea • Dimitrios Kloukos • Christos Katsaros • Anton Sculean
7Soft Tissue Augmentation at Maxillary and Mandibular Incisors in Orthodontic Patients
Dimitrios Kloukos • Theodore Eliades • Anton Sculean • Christos Katsaros
8Periodontal Considerations in Orthodontic and Orthopedic Expansion
Andrew Dentino • T. Gerard Bradley
9Surgical Lengthening of the Clinical Crown
Spyridon I. Vassilopoulos • Phoebus N. Madianos • Ioannis Vrotsos
10Management of Impacted Maxillary Canines
Marianna Evans • Nipul K. Tanna • Chun-Hsi Chung
SECTION III: ORTHODONTIC CONSIDERATIONS FOR THE PERIODONTIC PATIENT
11Clinical Evidence on the Effect of Orthodontic Treatment on the Periodontal Tissues
Spyridon N. Papageorgiou • Theodore Eliades
12Orthodontic Mechanics in Patients with Periodontal Disease
Carlalberta Verna • Turi Bassarelli
13Orthodontic Treatment in Patients with Severe Periodontal Disease
Tali Chackartchi • Stella Chaushu • Ayala Stabholz
Index
This book gathers the available evidence and offers a thorough and substantiated discussion of treatment for the ortho-perio patient. With contributions from leading scholars and clinicians all over the world, the book systematically analyzes the interaction of the two specialties from both scientific and clinical perspectives. It includes an introductory section where the fundamentals of oral physiology with relation to orthodontic-periodontic interactions are analyzed, including bone biology in adult patients and the basics of oral microbiota attachment and pellicle organization on materials. The subsequent section on periodontal considerations for the orthodontic patient covers the periodontal examination of the orthodontic patient, aspects of gingival recession and grafting, clinical attachment level, orthodontic-periodontic effects of expansion, surgical crown lengthening, and ectopic canine eruption. The last section on orthodontic considerations for the periodontic patient includes chapters on clinical attachment level, the biomechanics in compromised periodontal tissues, and principles of orthodontic treatment in periodontic patients.
The evidence provided in this book and the case series portraying the adjunct role of each specialty in the treatment planning of patients with periodontal or orthodontic needs furnish important theoretical and clinical information as well as practical guidelines to improve the treatment outcome of therapeutic protocols involving ortho-perio interventions. Thus, the book not only acts as a reference book on the topic but, more importantly, includes substantiated guidelines and validated treatment approaches, which aid the practicing clinician in individualized treatment planning. It is therefore appropriate for academics, clinicians, and postgraduate students in orthodontics and periodontology and could be used as an accompanying text for the standard seminar of specialty training in dental schools.
It may be worth noting that this book was conceived 7 years ago with an additional editor, the late Dr Vincent G. Kokich, who was instrumental in developing the scope of the text and undertook the contribution of several chapters. With his sudden and tragic passing in 2013, the project had to be re-formed, and chapters were assigned to leading clinicians and academics in the field. The editors, who were fortunate to get acquainted with his brilliant clinical expertise and visionary academic and research service, return only a fragment of the debt they owe him for the collaboration they enjoyed by acknowledging his legendary path in the field.
Turi Bassarelli, MD, DDS, MSC
Senior Research and Teaching Fellow
Department of Orthodontics and Pediatric Dentistry
University Center for Dental Medicine
University of Basel
Basel, Switzerland
Georgios N. Belibasakis, DDS, MSC, PHD, FHEA
Professor and Head of Division of Oral Diseases
Department of Dental Medicine
Karolinska Institute
Solna, Sweden
T. Gerard Bradley, BDS, MS, DR MED DENT
Dean and Professor of Orthodontics
School of Dentistry
University of Louisville
Louisville, Kentucky, USA
Tali Chackartchi, DMD
Senior Instructor
Department of Periodontology
Faculty of Dental Medicine
Hadassah and Hebrew University
Jerusalem, Israel
Stella Chaushu, DMD, PHD
Associate Professor and Chair
Department of Orthodontics
Faculty of Dental Medicine
Hadassah and Hebrew University
Jerusalem, Israel
Chun-Hsi Chung, BDS, DMD, MS
Associate Professor and Chair
Department of Orthodontics
School of Dental Medicine
University of Pennsylvania
Philadelphia, Pennsylvania, USA
Raluca Cosgarea, DDS, DR MED DENT
Assistant Professor and Research Fellow
Department of Periodontology
Faculty of Medicine
Philipps University of Marburg
Marburg, Germany
Carlos Marcelo da Silva Figueredo, DDS, MDSC, PHD
Associate Professor
Department of Dentistry and Oral Health
School of Periodontology
Griffith University
Brisbane, Australia
Andrew Dentino, DDS, PHD
Professor and Director
Department of Periodontics
Marquette University
Milwaukee, Wisconsin, USA
George Eliades, DDS, DRDENT
Professor and Head
Department of Dental Biomaterials
School of Dentistry
National and Kapodistrian University of Athens
Athens, Greece
Theodore Eliades, DDS, MS, DR MED SCI, PHD
Professor and Director
Clinic of Orthodontics and Pediatric Dentistry
Center of Dental Medicine
University of Zurich
Zurich, Switzerland
Marianna Evans, DMD
Clinical Associate
Department of Orthodontics
School of Dental Medicine
University of Pennsylvania
Philadelphia, Pennsylvania, USA
Private Practice
Newtown Square, Pennsylvania, USA
Anastasios Grigoriadis, DDS, PHD
Lecturer and Senior Dentist
Department of Dental Medicine
Division of Oral Diagnostics and Rehabilitation
Karolinska Institute
Huddinge, Sweden
Christos Katsaros, DDS, DR MED DENT, ODONT DR/PHD
Professor and Chair
Department of Orthodontics and Dentofacial Orthopedics
School of Dental Medicine
University of Bern
Bern, Switzerland
Dimitrios Kloukos, DDS, DR MED DENT, MAS, MSC
Head of Orthodontic Department
General Hospital of Greek Air Force
Athens, Greece
Research Associate
Department of Orthodontics and Dentofacial Orthopedics
School of Dental Medicine
University of Bern
Bern, Switzerland
Dimitrios Konstantonis, DDS, MS, PHD
Research Associate
Department of Orthodontics
School of Dentistry
National and Kapodistrian University of Athens
Athens, Greece
Research Visiting Fellow
Clinic of Orthodontics and Pediatric Dentistry
Center of Dental Medicine
University of Zurich
Zurich, Switzerland
Phoebus N. Madianos, DDS, PHD
Professor
Department of Periodontology
School of Dentistry
National and Kapodistrian University of Athens
Athens, Greece
Margarita Makou, DDS, MS, DRDENT
Professor Emeritus
Department of Orthodontics
School of Dentistry
National and Kapodistrian University of Athens
Athens, Greece
Spyridon N. Papageorgiou, DDS, DR MED DENT
Senior Teaching and Research Assistant
Clinic of Orthodontics and Pediatric Dentistry
Center of Dental Medicine
University of Zurich
Zurich, Switzerland
William Papaioannou, DDS, MSCD, PHD
Assistant Professor
Department of Preventative and Community Dentistry
National and Kapodistrian University of Athens
Athens, Greece
Christoph A. Ramseier, DDS, DR MED DENT
Senior Lecturer
Department of Periodontology
School of Dental Medicine
University of Bern
Bern, Switzerland
Giovanni E. Salvi, DDS, DR MED DENT
Associate Professor, Vice Chairman, and Graduate Program Director
Department of Periodontology
School of Dental Medicine
University of Bern
Bern, Switzerland
Anton Sculean, DDS, MS, DR MED DENT, DR HC
Professor and Chair
Department of Periodontology
School of Dental Medicine
University of Bern
Bern, Switzerland
Ayala Stabholz, DMD
Senior Dentist
Department of Periodontology
Faculty of Dental Medicine
Hadassah and Hebrew University
Jerusalem, Israel
Nipul K. Tanna, DMD
Assistant Professor
Department of Orthodontics
School of Dental Medicine
University of Pennsylvania
Philadelphia, Pennsylvania, USA
Spyridon I. Vassilopoulos, DDS, MSC, DRDENT
Assistant Professor
Department of Periodontology
School of Dentistry
National and Kapodistrian University of Athens
Athens, Greece
Carlalberta Verna, DDS, DR MED DENT, PHD
Professor and Head
Department of Orthodontics and Pediatric Dentistry
University Center for Dental Medicine
University of Basel
Basel, Switzerland
Ioannis Vrotsos, DDS, MSD, DRDENT
Professor and Director
Department of Periodontology
School of Dentistry
National and Kapodistrian University of Athens
Athens, Greece
Bone Biology and Response to Loading in Adult Orthodontic Patients
Dimitrios Konstantonis
Orthodontic movement is achieved due to the ability of alveolar bone to remodel.1–3 The bone-remodeling process is controlled by an equilibrium between bone formation in the areas of pressure and bone resorption in the areas of tension as the teeth respond to mechanical forces during treatment. The main mediators of mechanical stress to the alveolar bone are the cells of the periodontal ligament (PDL). The PDL consists of a heterogenous cell population comprised by nondifferentiated multipotent mesenchymal cells as well as fibroblasts. The periodontal fibroblasts have the capacity to differentiate into osteoblasts in response to various external mechanical stimuli. This feature of the PDL fibroblasts plays a key role in the regeneration of the alveolar bone and the acceleration of orthodontic movement.
Current research provides scientific data that elucidates the molecular response of the human PDL fibroblasts after mechanical stimulation.4–6 Integrins at focal adhesions function both as cell-adhesion molecules and as intracellular signal receptors. Upon stress application, a series of biochemical responses expressed via signaling pathway cascades, involving GTPases (enzymes that bind and hydrolyze guanosine triphosphate [GTP]), mitogen-activated protein kinases (MAPKs), and transcription factors like activator protein 1 (AP-1) and runt-related transcription factor 2 (Runx2), stimulate DNA binding potential to specific genes, thus leading to osteoblast differentiation. Consecutively, the activation of cytokines like receptor activator of nuclear factor κB ligand (RANKL) and osteoprotegerin (OPG) regulates osteoclast activity. Despite the importance of these biologic phenomena, the number of reports on the molecular response of human periodontal fibroblasts after mechanical stimulation and on the subsequent activation of signaling pathways is limited.
Age has a considerable impact on the composition and integrity of the periodontal tissues and, according to clinical beliefs and research studies, plays a significant role in the rate of orthodontic tooth movement.7–12 Apart from the observed cellular morphologic changes, the levels of proliferation and differentiation of alveolar bone and PDL cells also diminish with age. At a molecular level, aged human PDL fibroblasts show alterations in signal transduction pathways, leading to a catabolic phenotype displayed by a significantly decreased ability for osteoblastic differentiation, thus affecting tissue development and integrity.13,14 Currently, the difference in molecular response to orthodontic load among different age groups is considered of utmost importance. Still, the clinical application of biologic modifiers to expedite or decrease the rate of orthodontic tooth movement is underway.
Biology of Tooth Movement
ALVEOLAR BONE
The alveolar bone is the thickened ridge of the jaw that contains the tooth sockets, in which the teeth are embedded. The alveolar process contains a region of compact bone adjacent to the PDL called the lamina dura.15 When viewed on radiographs, it is the uniformly radiopaque part, and it is attached to the cementum of the roots by the PDL. Although the lamina dura is often described as a solid wall, it is in fact a perforated construction through which the compressed fluids of the PDL can be expressed. The permeability of the lamina dura varies depending on its position in the alveolar process and the age of the patient. Under the lamina dura lies the cancellous bone, which appears on radiographs as less bright. The tiny spicules of bone crisscrossing the cancellous bone are the trabeculae and make the bone look spongy. These trabeculae separate the cancellous bone into tiny compartments, which contain the blood-producing marrow.
The alveolar bone or process is divided into the alveolar bone proper and the supporting alveolar bone. Microscopically, both the alveolar bone proper and the supporting alveolar bone have the same components: fibers, cells, intercellular substances, nerves, blood vessels, and lymphatics. The alveolar bone is comprised of calcified organic extracellular matrix containing bone cells. The organic matrix is comprised of collagen fibers and ground substance. The collagen fibers are produced by osteoblasts and consist of 95% collagen type I and 5% collagen type III. The ground substance contains the collagen fibers, glycosaminoglycans, and other proteins. The noncalcified organic matrix is called osteoid. Calcification of the alveolar bone occurs by deposition of carbonated hydroxyapatite crystals around the osteoid and between the collagen fibers. Noncollagenous proteins like osteocalcin and osteonectin also participate in the calcification process.
The cells of the alveolar bone are divided into four types16:
•Osteoblasts: Specialized mesenchymal cells forming bone
•Osteoclasts: Multinucleated cells responsible for bone resorption
•Lining cells: Undifferentiated osteoblastic cells
•Osteocytes: Osteoblasts located within the compact bone
The alveolar bone is an extremely important part of the dentoalveolar device and is the final recipient of forces during mastication and orthodontic treatment. The reaction to these forces include bending of the alveolar socket and subsequent bone resorption and deposition, which depends on the time, magnitude, and duration of the force. Although the biologic mechanisms underlying these cellular changes are not fully known, it seems they resemble those of the body frame, where mechanical loading has osteogenic effects. Despite the similarities between the alveolar and compact bone, the different response to mechanical loading is attributed to the presence of the PDL, a tissue full of undifferentiated mesenchymal cells, which serves as the means through which the signal is transmitted to the alveolar bone.
CONTEMPORARY DATA ON BONE BIOLOGY
Recent studies report interesting findings on bone biology. Bone morphogenetic proteins (BMPs) are a group of growth factors, also known as cytokines, that act on undifferentiated mesenchymal cells to induce osteogenic cell lines and, with the mediation of growth and systemic factors, lead to cell proliferation, osteoblast and chondrocyte differentiation, and subsequently bone and cartilage production.17 Osteoblasts derive from nonhematopoietic sites of bone marrow that contain groups of fibroblast cells, which have the potential to differentiate into bone-type cells known as mesenchymal stem cells, skeletal stem cells derived from bone marrow, bone marrow stromal cells, and multipotent mesenchymal stromal cells.18
Bone is constantly being created and replaced in a process known as remodeling. This ongoing turnover of bone is a process of resorption followed by replacement of bone that results in little change in shape. This is accomplished through osteoblasts and osteoclasts. Cells are stimulated by a variety of signals, and together they are referred to as a remodeling unit. Approximately 10% of the skeletal mass of an adult is remodeled each year.19 The basic multicellular unit (BMU) is a wandering group of cells that dissolves a portion of the surface of the bone and then fills it by new bone deposition20 (Fig 1-1). The osteoblasts are dominant elements of the basic skeletal anatomical structure of the BMU. The BMU consists of bone-forming cells (osteoblasts, osteocytes, and bone-lining cells), bone-resorbing cells (osteoclasts), and their precursor cells and associated cells (endothelial, nerve cells).
Fig 1-1 The basic multicellular unit. Cells are stimulated by a variety of signals in order to start bone remodeling. In the model suggested here, the hematopoietic precursors interact with cells of the osteoblast lineage and along with inflammatory cells (mainly T cells) trigger osteoclast activation. After osteoclast formation, a brief resorption phase followed by a reversal phase begins. In the reversal phase, the bone surface is covered by mononuclear cells. The formation phase lasts considerably longer and implicates the production of matrix by the osteoblasts. Subsequently, the osteoblasts become flat lining cells that are embedded in the bone as osteocytes or go through apoptosis. Through this mechanism, approximately 10% of the skeletal mass of an adult is remodeled each year.
The bone is deposited by osteoblasts producing matrix (collagen) and two further noncollagenous proteins: osteocalcin and osteonectin. Activation of the bone resorption process is initiated by the preosteoclasts, which are induced and differentiated under the influence of cytokines and growth factors into active mature osteoclasts. Osteoclasts break down old bone and bring the end of the resorption process21 (Fig 1-2).
Fig 1-2 Histologic cross section through a PDL under mechanical load. D, dentin; C, cementum; B, alveolar bone. (Courtesy of Dr K. Tosios, National and Kapodistrian University of Athens, Greece.)
The cycle of bone remodeling starts with the regulation of osteoblast growth and differentiation, which is accomplished through the osteogenic signaling pathways. A hierarchy of sequential expression of transcription factors results in the production of bone. Undifferentiated multipotent mesenchymal cells progressively differentiate into mature active osteoblasts expressing osteoblastic phenotypic genes and then transform into osteocytes within the bone matrix or undergo apoptosis.
The following three families of growth factors show a considerable impact on osteoblastic activity22:
•Transforming growth factor βs (TGF-βs)
•Insulinlike growth factors
•BMPs
Growth factors act primarily through specialized intracellular interactions and interactions with hormones or transcription factors. They also act in response to the activity of glucocorticoids, parathyroid hormone, prostaglandin, sex hormones, and more. The BMPs induce the production of bone in vivo by promoting the expression of Runx2 in mesenchymal osteoprogenitor and osteoblastic cells and the expression of Osterix in osteoblastic cells. The TGF-βs play a crucial role in osteoblast differentiation by promoting bone formation through the upregulation of Runx2 while simultaneously reducing the levels of transcription factors that lead the cells to adipogenesis.
The absence or dysfunction of several transcription factors involved in bone metabolism leads to severe clinical deformities23 (Table 1-1).
Table 1-1 Clinical deformities resulting from transcription factor mutation
RUNX2 TRANSCRIPTION FACTOR
Runx2, also known as core-binding factor subunit α1 (CBF-α1), is a protein that in humans is encoded by the RUNX2 gene.24 Runx2 is a key transcription factor associated with osteoblast differentiation. This protein is a member of the Runx family of transcription factors and has a Runt DNA-binding domain. It is essential for osteoblastic differentiation in both intramembranous and endochondral ossification and acts as a scaffold for nucleic acids and regulatory factors involved in skeletal gene expression. The protein can bind DNA either as a monomer or, with more affinity, as a subunit of a heterodimeric complex. Transcript variants of the gene that encode different protein isoforms result from the use of alternate promoters as well as alternate splicing. Differences in Runx2 are hypothesized to be the cause of the skeletal differences (eg, different skull shape and chest shape) between modern humans and early humans such as Neanderthals.25
Mutations in this gene in humans have been associated with the bone development disorder cleidocranial dysplasia26,27 (Fig 1-3; see also Table 1-1). Other diseases associated with Runx2 include metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly. Among its related pathways are endochondral ossification and the fibroblast growth factor signaling pathway.28 Deactivation of the gene in transgenic mice (RUNX2-/-) leads to complete lack of intramembranous and endochondral calcification due to lack of mature osteoblasts.29 The mesenchymal cells in these animals retain the ability to further differentiate into adipocytes and chondrocytes.
Fig 1-3 (a and b) Volume rendering image of cone beam computed tomography data of an adult male patient diagnosed with cleidocranial dysplasia.
PERIODONTAL LIGAMENT
The PDL is a dense fibrous connective tissue 0.15 to 0.40 mm thick that occupies the space between the root of the tooth and the alveolus.16 The narrowest area of the PDL is at the midroot (fulcrum). The region at the alveolar crest is the widest area, followed by the apical region. The width is generally reduced in nonfunctional teeth and unerupted teeth, whereas it increases in teeth subjected to occlusal load within the physiologic limits and in primary teeth.
Histologically it presents a heterogenous, highly cellular structure comprised of a thick extracellular matrix with incorporated fibers arranged along the root30 (Fig 1-4). The tooth does not come in direct contact with the alveolar bone but recedes into the alveolus, where it is retained by the PDL fibers.31 These fibers act as shock absorbers and help the tooth withstand mastication forces and also respond to orthodontic load.
Fig 1-4 The PDL fibers are primarily composed of bundles of type I collagen fibrils. Their classification into several groups is made on the basis of their anatomical location. The principal fiber groups of the PDL are depicted here.
Like any other connective tissue, the PDL is composed of cells and extracellular components. The PDL cells comprise mainly fibroblasts (65%), which derive from undifferentiated mesenchymal cells with the ability to differentiate to preosteoblasts and cementoblasts; they produce collagen types I, II, and V. Additionally, they show similar characteristics to osteoblasts, like production of alkaline phosphatase (ALP) and osteocalcin, and response to 1,25 dihydroxyvitamin D3.
The possibility of differentiation of the PDL fibroblasts to preosteoblasts upon the application of orthodontic force plays an important role in bone remodeling.32 Recent investigations report that the PDL is a major source of multipotent mesenchymal stromal cells that could be used for in vivo tissue regeneration such as cementum and the PDL itself.33–37 The potential transplant of these cells, which may be detached with relative ease and then proliferate ex vivo, has significant therapeutic use on the restoration of periodontal breakdown in periodontic patients.
The rest of the PDL cells include cementoblasts, osteoblasts, osteoclasts, undifferentiated mesenchymal cells, and the epithelial rest cells of Malassez. The PDL cells play synthetic, resorptive, and defensive roles. They are also progenitor cells. The ground substance is a gel-like matrix that accounts for 65% of the PDL volume and comprises glycoproteins and proteoglycans. It contains 70% water and has a significant effect on the tooth’s ability to sustain load. Cellular components like the collagen fibers are embedded within this matrix. The collagen fibers according to their location are divided into transseptal, alveolar crest, horizontal, interradicular, oblique, and apical. The PDL supports and protects the teeth within the alveolus with simultaneous sensory, nutritive, and formative functions.31 The teeth are anchored into the alveolar process by Sharpey fibers, which are the terminal ends of the principal PDL fibers that insert into the cementum and the periosteum of the alveolar bone (Fig 1-5).
Fig 1-5 Higher magnification of the junction of the PDL with the bone. Sharpey fibers, which are the mineralized part of the thick fiber bundles (marked with an *), originate in the PDL and help anchor the tooth to the bone. In this histologic section, the mineralized bone (including the Sharpey fibers) appears magenta as compared to the purple color of the nonmineralized portions of the fibers. (Courtesy of Dr K. Tosios, National and Kapodistrian University of Athens, Greece.)
The integrity of the alveolar bone is also associated with the presence of the PDL. In extraction sites or in ankylosed teeth, the PDL is destroyed, and progressive absorption of the alveolar ridge occurs (Fig 1-6). The imbalance between osteoblasts and osteoclasts leads to degenerative bone activity. This is due to the reduction in the number of osteoblasts and the simultaneous increase in osteoclasts. In the continuous cycle of bone remodeling that takes place around the tooth alveolus, the PDL has a role of a continuous source of osteoblasts.
Fig 1-6 Panoramic radiograph of a 70-year-old man with excessive bone resorption in the edentulous areas.
Orthodontic Tooth Movement at the Molecular Level
Orthodontic movement is possible because of the bone remodeling of alveolar bone.1–3 The forces exerted by the wires on the teeth are transduced to the PDL, provoking cellular and extracellular tissue response. The theories of orthodontic tooth movement have shifted from the tissue and cellular levels to the molecular level. Bone remodeling is regulated by a balanced system of two types of cells—osteoblasts and osteoclasts—and includes a complex network of interactions between cells and extracellular matrix in the presence of hormones, cytokines, growth factors, and mechanical loading. Bone resorption and formation constitutes a single process leading to skeleton renewal while maintaining its structural integrity.
Orthodontic and orthopedic theory and practice have a lot in common. The biology of bone remodeling is the subject of both disciplines and requires an understanding of the mechanism of mechanical stress and the response of different types of cells present in and around the bones. However, in tooth movement there is involvement of the PDL, which differs from the bone in composition and remodeling properties. Upon normal activities such as moving, the physical skeleton is under periodic stress. The alveolar bone is under similar periodic stress during mastication, which during orthodontic treatment becomes continuous, resulting in its bend, remodeling, and consequently tooth displacement. Regarding the body frame, the stress-remodeling mechanism is not fully clarified, yet it appears that stress application is a primary factor of bone regeneration.38,39 The osteogenic response is attributed to the activation of the “calm” lining cells of the periosteum that do not require any kind of previous resorption phase.40–42 On the other hand, upon orthodontic movement, alveolar bone undergoes significant resorption and apposition, the degree of which is directly correlated to the volume, direction, and duration of the force applied. Clinical orthodontists taking advantage of this well-organized system of bone remodeling exert biologic forces to achieve tooth movements.
The study of the molecular mechanisms involved with mechanical loading of the PDL through the signal transduction pathways is of outmost importance. Studies related to the investigation of the mechanical properties of the PDL can be classified according to the characteristics and condition of the tissue (age, presence of disease) and the type of the applied force (direction, magnitude, rate, duration). The duration and the rate of the mechanical load, however, constitute the major distinguishing factor in the classification of research because of the direct clinical interest: Relatively short-duration forces are considered to take place in a sound system, whereas long-term forces represent parafunctional impact as in orthodontic movement.
The effect of mechanical stimulation of periodontal fibroblasts has been studied with different experimental models. These models are necessary to mimic clinical conditions either under mechanical stimulation (such as during orthodontic movement) or under the impact of physiologic functions (chewing, muscle and tongue movements, etc). In the static model, fibroblasts are cultured in collagen substrates that can be stressed or are placed on petri dishes with a flexible membrane on the bottom and then positioned on top of a convex surface (Fig 1-7). In the latter model, stretch application can vary, being more intense at the center of the dish than at the periphery.4–6,24,43–45 Furthermore, a dynamic model is employed to investigate the fibroblasts’ response to cyclic mechanical stress (Fig 1-8). A special device is driven by an electric motor generating cyclic stress. A piston on which flexible silicone culture dishes are attached moves at desired frequencies. The output stress is transferred to the adherent fibroblasts, the properties of which are subsequently investigated.46
Fig 1-7 Static model of mechanical stimulation. A, flexible rectangular silicone dish; B, calibrated plate indicating the applied deformation of the silicone dish; C, direction of applied force.
Fig 1-8 Dynamic model of mechanical stimulation. The purpose of the device is the mechanical stress transfer to cells attached to the bottom of flexible silicone culture dishes. The device is driven by an electric motor and generates cyclic mechanical stress to the specially designed silicone plates. Thereby, the mechanical stress is transferred to the adherent human PDL cells. The effect of the cyclic mechanical stimulation on cells is further studied by Western blot analysis and quantitative real-time polymerase chain reaction, allowing the researcher to analyze the effects of mechanical stress on the cells.
Early research on the signaling pathways showed that an immediate result of the mechanical stress to the cells was the production of prostaglandins and secondary messengers cyclic adenosine monophosphate47,48 and inositol phosphates.49 Additionally, other authors reported changes in intracellular calcium (Ca2+) after activation-stretching of ion channels.50,51
SIGNAL TRANSDUCTION PATHWAYS
Bone formation
In recent years, the investigation of bone-specific mechanical load-related signaling pathways has attracted researchers’ attention. Cells inside the tissues as well as in cell cultures are connected with the extracellular matrix or their substrate by specialized sites of cell attachments called focal adhesions.52 Through specialized proteins called integrins, the actin-associated cytoskeletal proteins are linked to the extracellular matrix.53 Integrins are composed of structurally distinct subunits (α and β) that in combination form heterodimeric receptors with unique binding properties for collagen, vitronectin, laminin, etc. In the focal adhesions, integrins link the actin-associated proteins (talin, vanculin, α-actinin) and signaling molecules such as focal adhesion kinase and paxillin to the structural molecules of the extracellular matrix as well as to the outer surfaces of adjacent cells. Actions that cause disturbances in this link generate cellular responses associated with migration, proliferation, and differentiation.54,55 Consequently, integrins function as cell adhesion molecules and intracellular signal receptors.
Mechanical load applied to cells causes perturbation of the cell-to-cell and to cell-to–extracellular matrix attachment, acting as a signal to initiate further biochemical responses of the cell. Integrins serve as mechanoreceptors, and the stress fibers are necessary for the transduction of applied forces.56 Scientific data provide evidence that changes in cell signaling in response to mechanical stimulation are downstream of events mediated by integrins at focal adhesions.57–59
Once the cells recognize mechanical perturbation, they start transmitting the signal intracellularly through the cytoskeleton, mechanosensitive ion channels, phospholipids, and G-protein coupled receptors in the cell membrane. The low–molecular weight, small GTP-binding proteins of Ras-related GTPases, Rab and Rho, as well as the MAPK subtypes that are components of integrin-mediated signaling have been shown to be altered in mechanically stretched PDL fibroblasts.5,6,60,61 Research data have shown that signaling through the MAPKs is essential for the early stages of osteoblastic differentiation. To this end, there is evidence that low levels of continuous mechanical stress of human PDL cells induce rapidly the principal constituents of the transcription factor AP-1, c-Jun and c-Fos.24,61–63 Activation of the transcription factor AP-1 via extracellular signal-related kinase (ERK)/c-Jun N-terminal kinase (JNK) signaling enhances its DNA-binding activity on osteoblast-specific genes, hence moderating their expression rate. As a result, a shift toward differentiation occurs, marking the onset of the osteoblast phenotype.
Bone is formed by osteoblasts, which derive from undifferentiated mesenchymal cells. It has been postulated recently that the main regulator of osteoblastic differentiation is transcription factor CBF-α1 or Runx2, a member of the Runx transcription family. Runx2 binds to the osteoblast-specific cis-acting element 2 (OSE2), which is found in the promoter regions of all the major osteoblast-specific genes (ie, osteocalcin, osteopontin, bone sialoprotein, collagen type I, alkaline phosphatase, and collagenase-3) and controls their expression. Apart from this key role in osteoblast differentiation and skeletogenesis, Runx2 was also found to be a fundamental sensor of mechanical stimulation applied to PDL fibroblasts. Direct upregulation of the expression and binding activity of Runx2 occurs after low-level mechanical stretching of the PDL cells.24,63 This effect is mediated by stretched-triggered induction of ERK-MAPK, as this kinase was found to physically interact and phosphorylate endogenous Runx2 in vivo, ultimately potentiating this transcription factor. These data provide a link between mechanical stress and osteoblast differentiation.
Recent research suggests that another transcription factor, polycystin-1 (PC1), may play an important role in skeletogenesis through regulation of the bone-specific transcription factor Runx2. Furthermore, PC1 colocalizes with the calcium channel polycystin-2 (PC2) in primary cilia of MC3T3-E1 osteoblasts.64,65 These findings indicate that PC1 regulates osteoblast function through intracellular calcium-dependent control of Runx2 expression. The overall function of the primary ciliumpolycystin complex may be to sense and transduce environmental clues into signals regulating osteoblast differentiation and bone development. It is recently postulated that PC1 acts as the chief mechanosensing molecule that modulates osteoblastic gene transcription and hence bone-cell differentiation through the calcineurin/NFAT (nuclear factor of activated T cells) signaling cascade.66,67
The signaling pathway cascade activated after the application of mechanical stimuli in the undifferentiated mesenchymal PDL cells with the potential to differentiate to osteoblasts can be summarized as follows4–6,24,60–63 (Fig 1-9):
Fig 1-9 Signal transduction pathways under mechanical stress exerted by orthodontic archwires.
1.Disturbances in cell attachment through integrins at focal adhesions.
2.Transmission to the cytoplasm via small GTPases (Rho and Rab).
3.Triggering of the MAPK (ERK/JNK) cascades.
4.Activation of bone-specific and bone-related factors Runx2, c-Jun, and c-Fos.
5.Binding of these transcription factors to the OSE2 at the promoter regions of all major osteoblastic genes (OC, OPN, ALP, BSP, COL I, MMP13), thus controlling their expression.
Ultimately these biochemical cascades result in changes to gene expression and reprogramming of the cells toward an osteoblast phenotype.
Bone resorption
The cycle of this orthodontic force-induced bone remodeling is maintained through the existence of the PDL. It is apparent that the PDL with its pluripotent cell population acts as a provider of undifferentiated cells, which under mechanical stress differentiate into osteoblasts. Then mature osteoblasts induce osteoclast differentiation and bone resorption activities by the production of cytokines (ie, RANKL and OPG). Furthermore, nitric oxide (NO), prostaglandins, and tumor necrosis factor-α (TNF-α) also induce osteoclast differentiation and bone resorption.68–70 In vitro studies suggest that while certain cytokines produced by osteocytes activate osteoclast precursors in the PDL at the resorption site, NO inhibits osteoclast activity at the opposite site in rats.71
Actual bone resorption is preceded by degradation of the nonmineralized layer of the osteoid by the osteoblasts. Only after this layer is degraded through matrix metalloproteinase (MMP) activity can the differentiated osteoclasts attach to the bone surface.72,73 This attachment is regulated by increased levels of osteopontin found at the resorption site, produced by osteoblasts and osteocytes.74,75
Cytokines are proteins produced by connective tissue cells such as fibroblasts and osteoblasts. These low–molecular weight proteins (<25 kDa) regulate or modify the action of other cells in an autocrine or paracrine mode. The synthesis and action of cytokines is controlled by systemic hormones and mechanical stimuli. Among the first recognized bone-related cytokines are interleukin-1 (IL-1) and TNF, both stimulating bone resorption in vitro.76–78 It is evident that the study of their role will provide important information regarding remodeling procedures and will in particular clarify the interaction between osteoclasts and osteoblasts.
RANKL, which is a member of the membrane-associated TNF ligand family, is considered a cytokine of great importance, playing a vital role in osteoclast formation and function.79,80 Osteoclast precursors and osteoclasts express the receptor of RANKL (ie, RANK) on which RANKL binds, inducing osteoclast differentiation. Other transcription factors involved in resorption activities such as parathyroid hormone, IL-1, IL-6, and TNF-α act by upregulating RANKL expression by osteoblast precursors and osteoblasts.
With regard to bone remodeling, a pivotal role is similarly attributed to OPG.81 Also produced by osteoblast precursors and osteoblasts, OPG inhibits osteoclast formation by competing with RANKL for the membrane receptor RANK. The equilibrium between RANKL and OPG, while maintained for purposes of tissue homeostasis, is disturbed when an orthodontic force is applied to the fibroblasts of the PDL (Fig 1-10). Of these two competing transcription factors, the prevailing one occasionally shifts the pendulum toward osteoclast or osteoblast activity.
Fig 1-10 The equilibrium between RANKL and OPG plays a pivotal role in bone remodeling.
In rats with experimental periodontitis, it was shown that the systematic administration of human OPG-Fc fusion protein inhibited the alveolar bone resorption by inhibiting the RANKL receptor.82 This may suggest an innovative therapeutic approach for the treatment of periodontitis in the future. Still, the local administration of OPG-Fc mesial to the first molars of Sprague-Dawley rats led to inhibited osteoclastogenesis and tooth movement at the targeted dental sites.83 Recent scientific data suggest that the biochemical interplay and its regulation by these two cytokines will enlighten the signaling pathway of orthodontic-induced bone remodeling and will allow for pharmacologic intervention in the future.84,85
THE ROLE OF INFLAMMATION IN TOOTH MOVEMENT
The issue of inflammation as a cellular response of tissues involved in orthodontic tooth movement has recently attracted researchers’ interest. Existing evidence showing that both cytokines (often referred to in the literature as mediators of inflammation or proinflammatory cytokines) and neurotransmitters such as calcitonin gene-related peptide and neuropeptide are involved in bone remodeling gave impetus to the theory that tooth movement is an inflammatory process.86,87
Research data show that mechanical stimulation in cells causes inflammatory responses similar to those caused by inflammation factors.88 In particular, nuclear factor κB (NF-κB) is found in stimulated bone cells.89 NF-κB is a transcription factor located in the cell nucleus that is present in all types of cells and involved in cellular responses to stimuli such as stress, cytokines, free radicals, ultraviolet radiation, and bacterial or viral antigens. In addition, NF-κB plays an important role in the immune response to infection and as a transcription factor in the regulation of genes involved in growth and development. Accordingly, erroneous regulation of NF-κB is associated with carcinogenesis, inflammatory and autoimmune reactions, septic shock, viral infections, and inappropriate immune development. Inhibition of NF-κB has been recently suggested in the course of inflammation and cancer treatment.90,91
Because inflammation is a localized host response to microbial infection or to cell distraction, one could argue that when biologic forces are applied, tooth movement is an aseptic process. If any potential tissue damage occurs, it is due solely to the exaggerated magnitude of the exerted force. However, the description of the orthodontic movement as an inflammatory process gives the false impression that this may be a pathologic event. In attempting to describe in one sentence the response of tissues to orthodontic tooth movement, one could argue that it involves an exaggerated form of productive activity combined with foci of tissue repair, especially in loading and unloading zones adjacent to the PDL where bone and cementum remodel.
Effect of Age on Tissue Response and Remodeling
AGING AND BONE
All tissues, including bone, undergo changes in composition and morphology with age as well as changes at the cellular and molecular levels.92 Cortical bone becomes more brittle, bone density and elasticity are reduced, and there is less resistance to mechanical loads.93–96 Histomorphometric studies on human cadavers have suggested that with age, the region of osteoid covered by active osteoblasts is reduced along with the number of osteoclasts in bone-resorption surfaces. Also, it has been shown that age provokes degenerative morphologic changes in osteoblasts, which included size reduction and existence of pycnotic cores, while their ability to proliferate was diminished.97 More recent studies corroborated that osteoblast and osteoclast differentiation decreases with age.98,99
The changes observed at the cellular and molecular levels in bone may be associated with decreased ability of cells to respond to mechanical stress, thus reducing the rate of bone remodeling.100,101 At the molecular level, it is reported that aged osteoblasts show reduced levels of ALP expression, collagen type I, and osteocalcin.102 Several studies on alveolar bone osteoblasts conclude that the levels of proliferation and differentiation are reduced with increasing age.103 It was also reported that women present a reduced expression of the transcription factor Runx2 in bone marrow stromal cells, while RANKL levels are increased.103 In an experimental study in bone cells of adult mice, the gene expression levels presented in the Wnt signaling pathway were decreased when compared with their young counterparts.104
Osteoporosis
Osteoporosis is the most common age-related metabolic bone disease with severe social and economic impact and high morbidity and mortality. It is characterized by a decrease in bone mass, disorder of the bone microarchitecture, decreased strength, and increased fracture rates (Fig 1-11). Bone loss occurs due to excessive osteoclast activity and decreased osteoblast activity. Recently it has been shown that osteoblastic activity may be promoted by mechanical stimulation of the osteoblasts. Osteoporosis is an established and well-defined disease that affects more than 75 million people in Europe, Japan, and the United States and causes more than 2.3 million fractures annually in Europe and the United States alone.105
Fig 1-11 CBCT of the mandibular right lateral incisor area of a 55-year-old woman. The altered bone density and microarchitecture are due to osteoporosis. (Courtesy of Dr S. Petsaros.)
Osteoporosis may be due to lower-than-normal peak bone mass and greater-than-normal bone loss. The deregulation of bone remodeling can be attributed to several factors like hormone levels, diet, physical status, and a number of diseases or treatments including alcoholism, anorexia, hyperthyroidism, surgical removal of the ovaries, and kidney diseases. Also, certain medications increase the rate of bone loss, including antiepileptic drugs, chemotherapy, and steroids.
Reduction of mechanical load on bone inhibits osteoblast-mediated bone formation and accelerates osteoclast-mediated bone resorption and leads to what has been called disuse osteoporosis. Disuse osteoporosis is caused by lack of normal physical activity, immobilization, or long-term bed rest and affects an ever-increasing number of people around the world. Studies show that osteoblasts in disuse osteoporosis cannot proceed to normal-level bone synthesis after the osteoclast activity, thus resulting in significant bone loss.106 Osteoporosis is clinically defined as a bone density 2.5 standard deviations below that of a young adult. This is typically measured by dual-energy x-ray absorptiometry at the hip.105
Recently it has been shown that women at menopause with osteoporosis present with statistically significantly higher periodontal index scores than those without osteoporosis. Gingival retraction was also significantly higher in women at menopause with osteoporosis than in the control group. There was thus reported a real correlation between bone mineral density (BMD) and periodontal index, while no correlation was shown between BMD and dental mobility.107
Altered mechanotransduction signaling pathways have been shown to result in deregulated bone remodeling in osteoporosis.108109110