IP Indian Journal of Orthodontics and Dentofacial Research 2020;6(4):216–221

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Review Article
Biomarkers in orthodontics: A review

Nausheer Ahmed1 , K Ranjan R Bhat1, *, Rithika Joseph1 , Abrar Younus A1

1 Dept. of Orthodontics and Dentofacial Orthopaedics, Government Dental College and Research Institute, Bangalore,
Karnataka, India

ARTICLE INFO ABSTRACT

Article history: The examination of Gingival crevicular fluid (GCF) may be considered an acceptable way to depict the
Received 24-09-2020 biochemical changes occurring during orthodontic tooth movement. Correlating the changes taking place
Accepted 05-11-2020 in GCF with different types of orthodontic forces, the patient can be managed based on individual patients’
Available online 18-11-2020 tissue response. Thus, this can be an effective way of improving treatment efficiency and results. There is
little evidence regarding which GCF biomarkers are associated with the growing phase. Most of the earlier
reports provide information about correlation of GCF biomarkers with inflammation, bone remodeling and
Keywords: tissue damage and other processes associated with orthodontic tooth movement. This method is not being
Biomarkers clinically used to its full diagnostic potential and requires further studies to provide additional data.
Gingival crevicular fluid (GCF)
© This is an open access article distributed under the terms of the Creative Commons Attribution
License (https://creativecommons.org/licenses/by/4.0/) which permits unrestricted use, distribution, and
reproduction in any medium, provided the original author and source are credited.

1. Introduction 1.1. Biomarkers

A biomarker is a substance that can be measured and
Orthodontic tooth movement occurs due to complex
evaluated to depict or indicate normal biologic, pathogenic
interactions and interplay between alveolar bone,
or pharmacologic response to a therapeutic intervention. 6
periodontal ligament (PDL) cells. The inflammatory
High specificity and sensitivity are 2 main characteristics
changes produced by orthodontic forces lead to tooth
that should be associated with a good biomarker. The
movement and remodeling changes. 1 An expression of this
treatment duration can be shortened by acquiring knowledge
phenomenon is found in the GCF of the teeth being moved.
about the type of cellular process, which, in turn will help in
There is an increase in concentration of neurotransmitters,
using optimum force levels. 2
growth factors, cytokines etc. Orthodontic forces disrupt the
homeostasis of the extracellular matrix of PDL and alters
1.2. Metabolic products of paradental remodeling
composition of GCF. GCF can be labelled as a transudate
or an exudate. 2 Analysing the biomarkers, allows for a 1.2.1. Markers of orthodontic tooth movement
better understanding of the PDL changes associated with 1.2.1.1. Glycosaminoglycans. Extracellular matrix of
movement of teeth. The vascular changes and leucocyte connective tissues contains Glycosaminoglycans (GAGs). 7
infiltration bring about the remodeling of alveolar bone The GCF volume increases and reduces during retention
during orthodontic tooth movement. 3,4 These changes due to changes in gingival inflammation during orthodontic
depend upon the amount, direction and duration of force tooth movement. The GAGs, chondroitin sulphate levels
applied. 5 change during retention. 8 During orthodontic treatment,
the levels of chondroitin sulphate change in the deeper
periodontal tissues and PDL. Samuels et al showed that
* Corresponding author. the levels of GAG varied depending on the type of tooth
E-mail address: [email protected] (K. R. R. Bhat). movement. Monitoring the levels of Chondroitin sulphate

https://doi.org/10.18231/j.ijodr.2020.043
2581-9356/© 2020 Innovative Publication, All rights reserved. 216
 Ahmed et al. / IP Indian Journal of Orthodontics and Dentofacial Research 2020;6(4):216–221 217

during orthodontic tooth movement is helpful in obtaining 1.5. Inflammatory mediators

optimum treatment results. 9
1.5.1. Prostaglandin E
Table 1: Phases of orthodontic tooth movement (Pilon et al) Prostaglandin E2 (PGE2) is a compound that is
Phase 1 24H-2Days Acute inflammatory derived from arachidonic acid and acts along with
Initial Initial tooth response proinflammatory hormones as a potent biochemical
movement Vasodilation-migration of mediator of inflammation. The level of Prostaglandin
within the leucocytes-release of E2 increases during orthodontic tooth movement and is a
socket. cytokines-cell signalling marker of bone resorption. Application of Orthodontic force
molecules (metabolic
stimulates the cells in the local environment to synthesize
products of paradental
remodeling) and secrete Prostaglandin E2, which, in turn, will bring
Phase 2 20-30 days Chronic inflammation about osteoclastic bone resorption. 18 Ineterleukin-1
Arrest Movement Continuation of migration controls the production of Prostaglandin E2. Prostaglandin
stops of leucocytes Paradental E2 levels in Gingival crevicular fluid were found to be
remodeling highest 1 day after force application and reduced to normal
Phase 3 40 days of Another period of acute levels within 7 days. 19,20
Acceleration accelerated inflammation
tooth superimposing the
movement on-going chronic 1.5.2. Neuropeptides (calcitonin related gene peptide and
after initial inflammation substance p
force
According to Rosenfeld et al. substance P and CRGP
application
Phase 4 Overall tooth Recruitment of
coexisted in the sensory ganglion neurons having a small
Linear movement macrophages, fibroblasts, to medium diameter. In cats, there was an increase in
osteoblasts, and osteoclasts. nasal blood flow which was concentration dependant
Alkaline phosphatase when substance P or CRGP was infused in the local
activity arteries (Stjarne et al, 1989). According to Wakisaka, in
cat’s pulp, the sub-odontoblastic zone showed CRGP like
immunoreactivity in nerves along blood vessels. The dental
pulp in cats underwent vasodilation which was 10 times
1.3. Osteocalcin
more when CRGP was administered after substance P
Osteocalcin (OC) is an important component in the than before it (Gazelius et al, 1987). Intensified CRGP
extracellular matrix of bone. 10 It is a specific biomarker immunoreactivity was seen 5 days after commencement of
produced by osteoblasts and correlates with active molar movement and was present mainly in the tension
osteoblastic activity. 11 Structurally, osteocalcin binds to site. In cats, following orthodontic force application to the
collagen and apatite present in bone and helps in maxillary canines at intervals of 1hr, 2 days, 7 days, 28 days,
remodeling of bone. The GCF of patients with periodontal a similar pattern of increase in cellular staining for CRGP
disease presents with osteocalcin and an increase in its was observed (Okamoto et al, 1991). Neurotransmitters
concentration has been shown to be associated with higher such as Substance P, VIP and CRGP may play a dual
rates of bone turnover. 12,13 role in the mechanically stressed periodontium. One being,
its action on the endothelial cells thereby promoting
1.4. Matrix metalloproteins 1 and 8 vasodilation and facilitating diapedesis, and the other
being, the regulation of neuropeptides and its activity after
In pathological and physiological conditions, the PDL introducing them to specific receptors following release
remodeling is mainly controlled by the enzyme Matrix from sensory nerve endings.
metalloproteinases (MMPs). Osteoclasts cause bone
resorption by demineralization of the inorganic portion of 1.6. Interleukin-1 (receptor antagonist) 1β ,2,6,8
bone by acid and degradation of organic component of bone
by cathepsin K and MMPs. 14,15 Collagenase-1 (MMP-1) Many cell types, such as fibroblasts, osteoclasts
and collagenase-2 (MMP-8) are matrix metalloproteinases and polymorphonuclear leukocytes (PMNs) release
that initiate tissue remodeling by cleaving native triple- proinflammatory cytokines, one of which is Interleukins
helical interstitial collagen. An experiment done on (ILs). The production of Interleukins is time dependant
dogs demonstrated an increase in MMP-1 levels during and are released during periodontal remodeling process
orthodontic force application, which later decreased after following orthodontic force application. 21 Interleukins
force removal. 16 However, there was inconclusive evidence are used as biomarkers to understand the metabolic
of MMP-1 in GCF of patients undergoing orthodontic processes associated with orthodontic tooth movement
treatment. 17 because, they play a role in normal physiologic turnover
218 Ahmed et al. / IP Indian Journal of Orthodontics and Dentofacial Research 2020;6(4):216–221

of bone and remodeling process following application 1.9. Enzymes of high cellular activity
of mechanical stress. 2–25 The Interleukins 1,6 and 8 are
proinflammatory interleukins, that can be found in the 1.9.1. β -Glucuronidase
GCF during orthodontic tooth movement. 26 Interleukin-1, b-glucuronidase is a lysosomal enzyme that is elevated
a proinflammatory cytokine that is produced by activated during degradation process of connective tissue and is
macrophages, monocytes, B-cells, neutrophils, fibroblasts, associated with release of primary granules from the
and epithelial cells, is a potent stimulator of bone resorption. neutrophils. A significant increase in b-glucuronidase levels
The interleukins play a role in the proinflammatory process, is seen 2 weeks after activation of orthodontic appliance. 36
wound healing and matrix degradation. 27 In response to
inflammation, many cells such as fibroblasts, epithelial 1.9.2. Aspartate aminotransferase and lactate
cells, endothelial cells and alveolar macrophages, produce dehydrogenase
and secrete Interleukin-8. The Interleukin-8 is a potent During apoptosis, Aspartate aminotransferase (AST)
proinflammatory cytokine which helps in recruitment is released from the cytoplasm into the extracellular
and activation of neutrophils throughout inflammation. environment. The amount of tissue destruction and bone
Therefore, inflammatory cells like neutrophils migrate remodeling occurring during orthodontic tooth movement
from the PDL capillaries to the inflammatory region. can be assessed by evaluating the increase in levels of AST
Interleukin-6 is a macrophage which originates from the in the GCF. 37,38 During apoptosis, Lactate dehydrogenase
T-cells. The accumulation of Interleukin-6 in the connective (LDH) present in the cytoplasm is released extracellularly.
tissue adjacent to the periodontal pockets affects healing of There is a Positive correlation existing between LDH levels
the periodontal pockets as a result of increased synthesis or and orthodontic tooth movement. 39–41
reduced release into the GCF. 28 Study reports have shown
that Interleukin-1b can stimulate bone resorption during 1.10. Enzymes and enzyme inhibitors
orthodontic tooth movement. 29–31
1.10.1. Cathepsin B
Cathepsin B (CAB) is a multifunctional biomarker and an
1.7. Tumour necrosis factor-alpha
intracellular lysosomal enzyme that initiates and maintains
Tumour necrosis factor-a (TNF-a) is a proinflammatory the inflammatory process. It is also associated with
cytokine that is derived from monocyte/macrophage and degradation of extracellular components like collagen. The
stimulates synthesis of proteolytic enzyme and osteoclastic levels of CAB are high, 1 day after starting orthodontic
activity. It is another proinflammatory cytokine that is treatment and corresponds to the inflammatory process
involved in bone resorption, acute and chronic inflammation occurring during tooth movement. 42 The CAB levels are
and has been investigated in orthodontic tooth movement. high even 1 month post orthodontic treatment due to the
Activated monocytes, macrophages, osteoblasts, epithelial collagen degradation and decomposing of exposed collagen
cells and endothelial cells produce tumour necrosis factor- fibers. 43
alpha. 32 Tumour necrosis factor-alpha is also an apoptotic
factor for osteocytes. This could function as a signal 1.10.2. Acid phosphatase and alkaline phosphatase
for osteoclast recruitment for bone resorption in the side Bone turnover can be assessed by monitoring acid and
undergoing PDL pressure. This also simultaneously inhibits alkaline phosphatase (ALP) activity in tissues. Bone
osteoblasts that are linked covalently in the native state to a resorption leads to an increase in in acid phosphatase
core protein to form proteoglycans. 33 activity, whereas, bone formation is associated with an
increase in alkaline phosphatase activity. 44 Typically,
alkaline phosphatase levels will be increased during
1.8. Receptor activator of nuclear initial stages of tooth movement, and an increase of
factor-kappa/receptor activator of nuclear factor-kappa acid phosphatase will occur in the later stages of tooth
ligand/osteoprotegerin system movement. 44

The salivary RANKL and OPG level seemed to correspond

1.11. Role of CCR2
with its levels in the GCF. This hypothesized the fact
that salivary RANKL and OPG were derived from the Regulation of bone remodeling during orthodontic tooth
GCF. The level of RANKL increased after each activation movement is carried out by Cytokines and chemokines.
appointment and corresponds to the time when active During mechanical loading, CC chemokine ligand 2 (CCL2)
tooth movement is taking place. The OPG levels reduced level is increased and functions to recruit osteoclasts.
during active tooth movement. Therefore, the RANKL/OPG Absence of CCR2 leads to a reduction of osteoclastic and
ratio increased post the activation appointment during osteoblastic activity. The CCR2-CCL2 axis is related to
orthodontic tooth movement. 34,35 osteoclast recruitment, bone resorption, and orthodontic
 Ahmed et al. / IP Indian Journal of Orthodontics and Dentofacial Research 2020;6(4):216–221 219

Table 2: List of GCF biomarkers and their role in orthodontic complex. 17 PC-1 deficient mice showed a difference in the
tooth movement osteoclastic activity, which was not reported earlier. This
Inflammatory mediators difference in osteoclastic activity may be due to lack of
Prostaglandin E-2 Bone resorption signal from the PDL. This suggests that PC-1 is involved
Substance P Bone resorption in osteoclast formation. 46
Epidermal growth factor Bone resorption
Transforming growth factor Bone remodeling
1.13. Colony stimulating factor
Rankl Stimulation of osteoclastic
differentiation They are glycoproteins which regulate the synthesis,
Osteoprotegerin Inhibition of osteoclastic maturation and function of monocytes and granulocytes.
differentiation Endothelial cells and fibroblasts synthesize M-CSF. Kahn
Granulocyte macrophage Bone turn over
and simmons demonstrated that osteoclasts can be produced
colony stimulating factor
Alpha-2 microglobulin Enhancer of IGF-1 by culturing M-CSF and bone marrow cells for 10 days.
Interleukin 1β ,2,6,8 Bone remodeling According to Takahashi, M-CSF is the most potent in
Myeloperoxidase-enzyme in Inflammation stimulating bone cells to produce osteoclasts. 47
PMN The above review of signal molecules that modulate
Metabolic products of paradental remodeling various steps of tissue remodeling introduces the
Hyaluronic acid Indicator of breakdown of orthodontist to the complexity and minute details of
gingival tissue events that appear to have major roles in this process.
Chondroitin sulphate Indicator of breakdown of Clinically, orthodontic patients might sense pain shortly
alveolar bone and PDL
after appliance activation. However, this feeling is just one
Pentaxrin-3 Marker of inflammation
of the many reactions on the cellular and molecular levels
Osteocalcin Bone turnover
Insulin growth factor Regulators of cell
that typify orthodontic tissue remodeling.
differentiation and apoptosis
Pyridinoline,deoxypyridinoline Indicators of bone 2. Conclusion
metabolism
N-telopeptide Bone resorption Numerous biomarkers have been reported to be found
Dentin matrix protein Root resorption in the GCF during the course of orthodontic tooth
Enzymes movement. These biomarkers provide vital information
Acid phosphatase Bone resorption about the micro-environment. The biomarkers in the GCF
Alkaline phosphatase Bone formation reflect the changes occurring during orthodontic treatment.
Aspartate amino transferase Cell necrosis Knowledge of biomarkers gives information about the
Cathepsin B Extracellular matrix proper choice of mechanical loading, which thereby helps
degradation in improving patient comfort and reducing treatment time.
Matrix metalloproteins(1,2,8) Breakdown denatured
collagen
3. Source of Funding
B glucuronidase Marker of granule release by
PMN No financial support was received for the work within this
Lactate dehydrogenase Indicator of cell death manuscript.
GCF: Gingival crevicular fluid, IGF-1: insulin like growth factor, GAG:
Glycosaminoglycans 4. Conflict of Interest
PMN: Polymorphonuclear neutrophils, TNF: Tumour necrosis factor,
PDL: Periodontal ligament The authors declare they have no conflict of interest.

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