Biological Aspect on Orthodontic

Tooth Movement

Abdillah Imron NasutionDept. Oral Biology-Faculty of DentistrySyiah Kuala UniversityAceh-Indonesia

Lecture:

Present: 4 Nov 2014

Dept. Orthodontic and Maxillofacial and Radiology

Suleyman Demirel University-Isparta

Turkey

INTRODUCTION� Tooth movement induced by orthodontic force application is

characterized by changes in the cells and tissue � When exposed to varying degrees of magnitude, frequency,

and duration of mechanical loading, cells and tissue show extensive macroscopic and microscopic changes.

� Orthodontic tooth movement, it was not just a cellular and tissue changes such as activation of osteoclasts or osteoblaststissue changes such as activation of osteoclasts or osteoblastsand other cells. however, it can also induce vascular change

� Based on this, the biological aspects during orthodontic tooth movement can be categorized:

1. TISSUE CHANGES2. CELL CHANGES3. VASCULAR CHANGES

Objective

� This presentation will describe the biological aspect that are involved during orthodontic tooth movement

1. TISSUE CHANGES

1.1 PERIODONTAL TISSUE

� The early response of periodontal tissues to mechanical stress involves several tissue changes that enable tooth movement. tooth movement.

� The periodontal tissues primarily affected by orthodontic forces can be divided histologically into two main regions:

a. the compression side (squeezed)

b. tension side (stretched)

� The compression region is an area that is pressed by the orthodontic appliance in the direction of the force.

� Compression results in the � Compression results in the deformation of disarrangement of tissues surrounding periodontal tissue.

� Subsequently, periodontal tissue changes may adapt to the compression force.

� Distortions in the normal periodontal fiber arrangement were observed

� Mechanical forces often cause hyalinisation leading to necrosis in the PDL and lead to bone resorption.bone resorption.

� Hyalinisation occurs as cell-free areas of the PDL, in which the normal tissue architecture and staining characteristics of collagen in the processed histologic material have been lost.

Figure Histological sections showing the periodontal ligament (PDL) of (a) non-hyalinized PDL at the pressure side, (b) hyalinizedPDL at the pressure side, and (c) PDL at the tension side. B, alveolar bone; T, tooth

� Numerous cell fragments (debris), areas of degraded matrix interspersed between the intact collagen fibrils and, in some cases, pyknotic nuclei were collagen fibrils and, in some cases, pyknotic nuclei were also present in hyalinisationareas

� Macrophages are ultimately responsible for removing the hyalinisedtissues.

The hyalinized zone (H) between the alveolar bone (B) and root (T) reveals a fi brillar structure. Resorption of alveolar bone occurs from the marrow spaces (arrows). Note the resorptionlacuna in the dentine at the periphery of the hyalinized zone (arrowhead).

� Alveolar bone resorption occurs at the compression areas during tooth movement.

� Bone resorption occurs through osteoclastic activity by osteoclast thus creating cavity in bone known as lacunae that later will be filled in by osteoblast cells to lacunae that later will be filled in by osteoblast cells to cover the cavity.

� Two processes involved in bone resorption: solubilisation of minerals and the degradation of the organ matrix (type I collagen).

� These processes are driven by proteolytic enzymes and, in particular, matrix metalloproteinases and and, in particular, matrix metalloproteinases and lysosomal cysteine proteinases

� As soon as the osteoclasts become inactive and move away from the bone surface, the compression areas display bone formation.

� In the tension region, new bone is formed as a result of forces during orthodontic treatment.

� Osteoblasts are differentiated from the local precursor cells, that is mesenchymal stem cells.

� Mature osteoblasts form the osteoids and the mineralisationosteoids and the mineralisationprocesses follow.

� In addition, endothelial nitric oxide synthase (eNOS) mediate the bone formation.

� During osteoblastic activity, also found alkaline phosphatase (ALP).

2. CELLS CHANGES

� Cellular changes that occur in orthodontic tooth movement consists of the development of stem cells, and two cells that involved in bone formation and involved in bone formation and resopsion.

� The cells are osteoblasts and osteoclasts

� There are facts that can be known as the biological aspect of these cells changes

2.1 Development of Stem Cells� The pressure-tension theory associated with OTM states

that the application of physiologic force, including compressional and tensional changes to the periodontal ligament (PDL), will activate mesenchymal stem cells.

� The PDL progenitor cells that experience force will differentiate into compression-associated osteoclastsdifferentiate into compression-associated osteoclastsand tension-associated osteoblasts, causing bone resorption and apposition, respectively.

� The multipotent mesenchymal stem cells begin their differentiation within hours of orthodontic force application

Osteoclasts Form from the Hematopoietic (Blood) Cell Lineage

Osteoclast

2.2 Osteoblasts� Migration of mesenchymal stem cells

from blood vessel walls, mesenchymal stem cell precursor activation, and preosteoblastformation

� Osteoblast differentiation by � Osteoblast differentiation by expressed transcription factor

� TF is involved in bone formation and induces mature osteoblasts to express osteocalcin

� Osteocalcin will inhibit osteoblastdifferentiation

� BMPs that bind to surface receptors on progenitor and mature osteoblasts trigger a signalling pathway that promotes osteoprogenitor cell differentiation and the upregulation of osteoblast activity

� Surface receptors on osteoblasts, stimulating � Surface receptors on osteoblasts, stimulating Growth Factor to regulate cell growth and development

� Osteoblastic enzymes: type I procollagen

� Procollagen will produce two types: procollagentype I C-terminal propeptide (PICP) and procollagentype I N-terminal propeptide (PINP)

� Procollagen Trigger a multilevel cascade of signal transduction pathways, prostaglandin E2 (PGE2) pathway: initiate structural and functional changes in extracellular, cell membrane, and cytoskeletal proteins

� Inhibition of NO production increases osteoclastogenesis and osteoclastic activity

� Nitric oxide (NO) is an important regulator of bone responses � Nitric oxide (NO) is an important regulator of bone responses to mechanical stress and is produced through the activity of constitutive endothelial nitric oxide synthase (eNOS) or inducible nitric oxide synthase (iNOS)which activated by IL-1 and TNF α

� NO mediates adaptive bone formation, protects osteocytesagainst apoptosis and mediates osteoclastic activity

2.3 Osteoclast� Osteoclast is specialised

multinucleated giant cells that originate from haematopoietic stem cells

� Osteoclastogenesis has been shown to be regulated primarily by the cytokines RANKL (Receptor cytokines RANKL (Receptor Activator of Nuclear Factor Kappa B Ligand) and M-CSF (macrophage colony-stimulating factor)

� RANKL is produced by osteoblastprecursors and binds to the RANK receptor on osteoclast progenitors in order to activate them for further differentiation

Bone

� This coupling can be competitively inhibited by OPG (osteoprotegerin), which binds to RANKL on an osteoblastprecursor

� Mediates osteoclastic activity of NO production increases osteoclastogenesis and osteoclastic activity

� Smaller osteocalcin (noncollagenous matrix protein) fragments are thought to be a degradation products of bone matrix

3. VASCULAR CHANGE� In vascular changes there are some aspects of biology

that have been reported.

� This fact is still needs to be explored in detail.

� In some research reports, aspects of vascular changes initiated by hypoxia conditions.

� These circumstances would trigger some other � These circumstances would trigger some other biological aspects such as apoptosis and angiogenesis.

� Involvement of endothelial cells and growth factors demonstrate the complexity of aspects that occur during this orthodontic tooth movement.

� Ultimately this process will trigger the inflammatory process

Hypoxia

� The early response of periodontal tissues to mechanical stress involves several metabolic changes that enable tooth movement

� Metabolic changes can occur to the cells of the periodontal ligament as a result of hypoxia

� Hypoxia describes oxygen deficiency in tissue due to oxygen partial pressure reduced beyond the physiologic level .partial pressure reduced beyond the physiologic level .

� Hypoxia influences cellular energy levels by reducing glycolytic activity and ATP production. The cells respond to hypoxia by expressing cellular mediators, particularly the hypoxia-inducible factor 1 (HIF-1), a heterodimer composed of HIF-1� and HIF-1�.

� HIF-1 induces apoptosis to inhibit hypoxia-induced mutations in cells by triggers the expression of the proapoptoticnineteen kD interacting protein-3 (Nip3).

� HIF-1 able to activate genes, such as the apoptosis-regulator Bax, that initiate cell death or stop proliferation.

� The formation of HIF-1 is limited by the subunit HIF-1�.� During hypoxia, the stabilized HIF-1� aggregates and binds to

HIF-1� creating the active transcription factor HIF-1 that can promote angiogenesis, stimulate cell proliferation, and is able to prevent cell death.

�

�

to prevent cell death. � The induction of HIF-1� will stimulate vascular endothelial

growth factor (VEGF), and the upregulation of RANKL directly correlated with the HIF-1� level .

� RANKL known produced by osteoblast precursors and binds to the RANK receptor on osteoclast progenitors in order to activate them for further differentiation

� In summary, hypoxia seems to fundamentally contribute to bone remodeling processes

Angiogenesis

� VEGF is known as one of the most important mitogen that induces angiogenesis. By adhering to receptors of endothelial cells, VEGF activates signal cascades, resulting in a broad variety of cellular and in a broad variety of cellular and vascular reactions.

� Via the expression of nitric oxide (NO), VEGF is also able to indirectly modulate vasodilation.

� NO plays a crucial role in a variety of biological processes, for instance, the regulation of vasodilation, blood flow, and inflammation

� In cells without HIF-1� (non hypoxia area). PDL cells suffering hypoxia release biochemical mediators (Chemokines) to induce leucocyte chemotaxis and cellular activation, leading to cell proliferation and angiogenesis.

� Mechanism of action of angiogenesis through endothelial cell receptor interaction are: ATP Synthase, angiomotin, and integrinsαvβ.αvβ.

Adenosine triphosphate (ATP) synthase

� ATP synthase is an enzyme complex that is located on the matrix side of the inner mitochondrial membrane.

� In some literature, ATP synthase referred as F1- F0 ATPase.

� The main function of ATP synthase is closely related to two constituent units of the F0 and F1. The unit serves as a medium F0 proton channel in the ATP synthase complex electron transfer, whereas the F1 unit serves as a catalytic synthesis of ATP from ADP and phosphate for cellular energy. catalytic synthesis of ATP from ADP and phosphate for cellular energy.

� F0 part consists of four types of polypeptide chain subunits, whereas the F1 consists of five subunits, namely α, β, γ, δ, and ε.

� The main function of ATP synthase is closely related to two constituent units of the F0 and F1.

� Mechanisms of angiogenesis by ATP synthase is done with the influx of protons (H +) across the membrane.

� Proton flow through the F0 units will be distributed to the unit F1 catalytic synthesis of ATP from ADP and phosphate for cellular energy.

Angiomotin

� The process of angiogenesis can actually be regarded as cell motility.

� Angiomotin: an endothelial cell protein that is involved in endothelial cell motility. Angiomotin indicate important relationships between motility and cell migration.migration.

� This protrusion can be a sheet called lamellipodia, actin network consisting of a thick and a little micro-tubules.

� Other forms of protrusion shaped like, elongated structure

� Protrusion always form a unidirectional movement of Golgi body movement and centrosome positioning in front of the nucleus.

Integrin

� Integrin is a cell surface glycoprotein composed of two subunits, namely α and β subunits that form a heterodimer complex and embedded in the cell membrane

� Integrin receptor is one that induces cell adhesion complex.

� Contact between cells with the surrounding extracellular matrix.

� This process takes place through a variety of adhesion molecules, � This process takes place through a variety of adhesion molecules, adhesion receptors, and ligand to make cell adhesion complex possible.

� Cell adhesion complexes that form serves to stabilize cell motility that is always bound to the matrix extra seluler.

� Through its interaction with integrin αvβ3, there will be regulation Focal Adhesion Kinase (FAK) which required in the formation of cell adhesion complexes.

� Increased regulation of FAK signaling activates the phosphatidylinositol 3-kinase (PI3K) to the protein kinase B (PKB). (PI3K) to the protein kinase B (PKB).

� Thus, it can activate growth factors that would increase gene expression and creating cell proliferation.

� Increasing signal that transmitted by integrins αvβ3 and cell adhesion complex formation will reduce the activity of p53 and p21 expression that play a role in cell death or apoptosis

� Weak signal is transmitted by integrins αvβ3 and cell adhesion complex formation will increase the activity of p53 and p21 expression that play a role in cell death or apoptosis

Anaerobic Glycolisis� Metabolic changes can occur to the cells of the

periodontal ligament as a result of hypoxia and decreased nutrient levels.

� In hypoxic conditions, cells will rely on anaerobic glycolysis.

� Cells that adapt via metabolic changes will continue to live and cells that cannot adapt to the ischaemiclive and cells that cannot adapt to the ischaemiccondition will die

� Lactate dehydrogenase (LDH) and aspartateaminotransferase (AST) found outside cells during necrosis

� The dead cell will lyse, releasing all of its contents to the milieu and subsequently causing the activation of local inflammatory processes

CONCLUSION1. Biological aspects on tissue changes on orthodontic

tooth movement :

2. Biological aspect on cells change on orthodontic tooth movement:

hyalinization, Bone Resoption, & Bone Formation

development of stem cell, Osteoclast-osteoblastactivity

3. Biological aspect on vascular change on orthodontic tooth movement:

4. On the basis of sequential reactions and released substances, numerous substances have been proposed as biomarkers.

hypoxia and anaerobic glycolisis that stimulate angiogenesis and inflammation process