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.

1. Biological Aspect on Orthodontic
Tooth Movement
Abdillah Imron Nasution
Dept. Oral Biology-Faculty of Dentistry
Syiah Kuala University
Aceh-Indonesia
Lecture:
Present: 4 Nov 2014
Dept. Orthodontic and Maxillofacial and Radiology
Suleyman Demirel University-Isparta
Turkey

2. 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 osteoblasts
and other cells. however, it can also induce vascular change
Based on this, the biological aspects during orthodontic tooth
movement can be categorized:
1. TISSUE CHANGES
2. CELL CHANGES
3. VASCULAR CHANGES

3. Objective
This presentation will describe
the biological aspect that are
involved during orthodontic
tooth movement

4. 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)

5. The compression region is an
area that is pressed by the
orthodontic appliance in the
direction of the force.
Compression results in theCompression results in the
deformation of
disarrangement of tissues
surrounding periodontal
tissue.
Subsequently, periodontal
tissue changes may adapt to
the compression force.

6. 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) hyalinized
PDL at the pressure side, and (c) PDL at the tension side. B,
alveolar bone; T, tooth

7. 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 hyalinisation
areas
Macrophages are
ultimately responsible for
removing the hyalinised
tissues.
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 resorption
lacuna in the dentine at the periphery of the
hyalinized zone (arrowhead).

8. 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 tolacunae that later will be filled in by osteoblast cells to
cover the cavity.

9. 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 andand, 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.

10. 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 mineralisation
processes follow.
In addition, endothelial nitric oxide
synthase (eNOS) mediate the bone
formation.
During osteoblastic activity, also
found alkaline phosphatase (ALP).

11. 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 andinvolved 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

12. 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 osteoclasts
and tension-associated osteoblasts, causing bone
resorption and apposition, respectively.
The multipotent mesenchymal stem cells begin their
differentiation within hours of orthodontic force
application

14. Osteoclasts Form from the Hematopoietic (Blood)
Cell Lineage
Osteoclast

15. 2.2 Osteoblasts
Migration of mesenchymal stem cells
from blood vessel walls,
mesenchymal stem cell precursor
activation, and preosteoblast
formation
Osteoblast differentiation byOsteoblast differentiation by
expressed transcription factor
TF is involved in bone formation and
induces mature osteoblasts to
express osteocalcin
Osteocalcin will inhibit osteoblast
differentiation

16. 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, stimulatingSurface receptors on osteoblasts, stimulating
Growth Factor to regulate cell growth and
development
Osteoblastic enzymes: type I procollagen
Procollagen will produce two types: procollagen
type I C-terminal propeptide (PICP) and procollagen
type I N-terminal propeptide (PINP)

17. 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 responsesNitric 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 osteocytes
against apoptosis and mediates osteoclastic activity

18. 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 (Receptorcytokines RANKL (Receptor
Activator of Nuclear Factor Kappa B
Ligand) and M-CSF (macrophage
colony-stimulating factor)
RANKL is produced by osteoblast
precursors and binds to the RANK
receptor on osteoclast progenitors
in order to activate them for further
differentiation

19. Bone
This coupling can be competitively inhibited by OPG
(osteoprotegerin), which binds to RANKL on an osteoblast
precursor
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

20. 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 otherThese 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

21. 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 proapoptotic
nineteen kD interacting protein-3 (Nip3).

22. 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

23. 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 andin 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

24. 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 integrins
αvβ.αvβ.

25. 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.

26. 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.

27. 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.

28. 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.

29. 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

30. 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

31. 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 ischaemic
condition will die
Lactate dehydrogenase (LDH) and aspartate
aminotransferase (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

32. CONCLUSION
1. 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-osteoblast
activity
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