20

The Indonesian Journal of Dental Research

Proceeding of The Internatonal
Symposium on Oral and Dental Sciences
Agustn Wulan Suci Dharmayant

Review: Pyridinoline Cross Link as Biomarker
Alveolar Bone Destruction

Agustin Wulan Suci Dharmayanti
Biomedical Department, Dentistry Faculty-Jember University
Jember, East Java, Indonesia
agustinwulan.fkgunej@gmail.com

Abstract

Background: In Indonesia, prevalence of periodontal diseases was very high about 46 %. Periodontal
diseases caused alveolar bone destruction. When bacteria attacked, bacteria product and host response
stimulate collagen degradation, especially type 1 collagen.Collagen type 1 consisted pyridinoline cross
link. Collagen degradation product will be excreted in bloodstream and urine. These products have
advantage to detect alveolar bone destruction in periodontal disease early, because clinical and
rongentnologis examination can detect advanced stage of alveolar bone destruction in periodontal
diseases. Objective: The aim of this review was to know pyridinoline cross link as biomarker alveolar
bone destruction. Literature review: Alveolar bone tissue was mineralization connective tissue. Alveolar
bone can be destructed by dental plaque bacteria and also by host response. Dental plaque bacteria
stimulated PMN and MMP releasing at inflamed gingival area. They caused collagen fibers of alveolar
bone was degradated and caused releasing of pyridinoline crosslink in blood. Conclusion: Pyridinoline
crosslink can be used as biomarker of alveolar bone destruction.

Keywords: pyridinoline crosslink, collagen degradation, alveolar bone destruction, biomarker
Introduction
Periodontal disease is one of oral diseases that have high prevalent. Survey Kesehatan
Rumah Tangga (SKRT) showed the prevalent of periodontal disease is 46 % [1]. Periodontal
diseases are caused by plaque bacteria. They will stimulate host cells to produce
inflammatory mediators. Inflammatory mediators will cause collagen degradation of
alveolar bone, especially type I collagen [2]. Collagen degradation product of alveolar bone
will be excreted through gingival crevicular fluid (GCF). Pyridinoline cross link as crosslink of
collagen type I will excreted through GCF too. Pyridinoline crosslink is crosslink of collagen
type I that abundant fibers of collagen type I [1].
In periodontal diseases diagnostic, dentists generally use clinical and x-ray examination.
However, these examinations can just detect advanced stage of periodontal diseases.
Nowadays some researches develop examination procedures practically. They use biological
signs of our body or are called biomarker. Biomarker can be used for detecting of diseases
activity, predicting of diseases progressivity, and evaluating of treatment respond.
Biomarker can use samples from biofilm plaque, GCF, and saliva [3]. These biomarkers are
suggested available to detect periodontal diseases that related with collagen degradation of
alveolar bone. The aim of this study is to review pyridinoline crosslink as biomarker alveolar
bone destruction.
21
The Indonesian Journal of Dental Research
Proceeding of The Internatonal
Symposium on Oral and Dental Sciences
Agustn Wulan Suci Dharmayant
Review of Literature
Collagen type I degradation product
Organic matrix of alveolar bone is built by collagen. Alveolar bone organic matrix is mainly
composed by collagen. Collagen consists of three alpha polypeptide chains coiled together
to form a triple helix reinforced by pyridinium crosslink. There are 4 type of pyridinium
crosslink, such as pyridinoline, deoxypyridinoline, C telopeptidepyridinoline (ICTP) and N
telopeptidepyridinoline (INTP). In bone remodeling process, collagen and pyridinium cross
link will be degraded and excreted into blood and urine [4].
Pyridnoline is a pyridinium crosslink that bind collagen in bone and cartilage. Pyridnoline
will be decomposed in the collagen degradation process and excreted through the urine
and not undergo re-metabolized [5]Deoxypyridinoline is pyridinium crosslink that bind
collagen in ligament, dentine, and bone. Deoxypyridinoline levels in GCF, urine and serum
can be used to detect periodontitis in beagle dog that its periodontal tissue is bound by
ligature [6].Deoxypyridinoline is very specific for bone. It is caused 98% deoxypyridinoline in
urine is derived from bone and not re-metabolized [7].
ICTP is a derivative of the region of carboxyl-terminal telopeptide of type I collagen
containing pyridinoline and deoxypyridinoline. ICTP is involved in the synthesis of collagen
maturation and released into the extracellular matrix. ICTP is specific found in bone and
cartilage, and is not found in soft tissues such as skin. ICTP levels in GCF increases following
with loss attachment and alveolar bone destruction due to osteoclast activity [6]. INTP is
amino terminal telopeptide crosslink of collagen type I. INTP is almost in bone tissue. INTP
is a specific and sensitive marker of bone breakdown [8].
Alveolar bone destruction
Alveolar bone is part of the maxilla and mandible that formed and supported tooth socket.
Alveolar bone is formed from connective tissue mineralized. Alveolar bone is consisted
inorganic (67%) and organic (33%) matrixes. The organic matrix of bone is consists of 28%
collagen and 5% non-collagen. Organic constituent of bone collagen matrix is 90% collagen
type I and the rest is collagen type III and IV [9].
Alveolar bone will destruct due to overload of chewing process and plaque bacteria activity
in periodontal disease. Product plaque bacteria cause bone progenitor cell differentiation
to be osteoclasts and stimulates gingival cells to secrete inflammatory mediators.
Inflammatory mediators such as IL I-, IL I-, TNF- and PGE2 would cause decomposition
and degradation of collagen in alveolar bone tissue, especially collagen type I [2].

Biomarker
Biomarker is a parameter that can be used to measure the progression of the disease from
the initial to advanced phase and monitor the results of therapy. This parameter can be
either a change in the physical, chemical or biological. Biomarkers can be used as a way to
see the state of the patient in a state of sepsis, because it is non-invasive biomarker, pretty
fast, practical and individual.Before the widespread use, biomarker must take validation
test and have a qualifying condition. Terms validation characteristics are known, have a
good standardization, and accurate [10].
Analytical validity, Clinical validity, Clinical utility and Ethical (ACCE) show four key
framework as a requirement for molecular diagnostics and biomarkers, including (1)
analytic validity of a test is its ability to measure accurately the components cool and
reliability with the techniques used (2) clinical validity of the test is its ability to detect or
22
The Indonesian Journal of Dental Research
Proceeding of The Internatonal
Symposium on Oral and Dental Sciences
Agustn Wulan Suci Dharmayant
predict the presence or absence of disease or predisposition to a disease, (3) clinical
function test showed good results, and (4) test must be ethical, legal and have social
implications [11].

Discussion
Periodontal disease was a chronic inflammation of tooth supporting tissues. Periodontal
tissue was consisted gingiva, cementum, alveolar bone, and periodontal ligament.
Periodontal disease was started from inflammation in gingiva. If it was not treated, it would
lead to other periodontal tissue damage, including alveolar bone. Alveolar bone destruction
in periodontal disease was result of the interaction between plaque bacteria and the host
cell. Host cell response would be against lipopolysacharide (LPS) of bacteria. Host cell
released immune cells, such as monocytes, PMN, macrophages, and other cells. Immune
cells stimulated releasing of inflammatory mediators, such as TNF, IL-1, IL-6, and
prostaglandin E2 (PGE2). Inflammatory mediators and PMN triggered fibroblasts and
osteoclasts to increase the production of MMP [2]. MMP could destruct extracellular matrix
of bone, resulting in degradation of alveolar bone collagen, especially collagen type I
alveolar bone as the main constituent. MMPs, which can act as powerful collagen-
destroying enzymes, are produced by fibroblasts and PMNs. TNF, IL-1, and receptor
activator of nuclear factor-kappa B ligand (RANKL) are elevated in active sites and mediate
osteoclastogenesis and bone breakdown. Bone-specific markers, such as ICTP, are released
into the surrounding area and transported by way of gingival crevicular fluid into the sulcus
or pocket and serve as potential biomarkers for periodontal disease detection (figure
1)[12].























Figure 1. Releasing of pyridinium crosslink in alveolar bone destruction
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The Indonesian Journal of Dental Research
Proceeding of The Internatonal
Symposium on Oral and Dental Sciences
Agustn Wulan Suci Dharmayant
MMP would cause destruction to type I collagen fibers in the cementum, periodontal
ligament and alveolar bone. MMP had collagenase activity, especially in the process of
remodeling connective tissue containing collagen type I and III [13].Pyridinoline crosslink
was released into GCF as soon as the beginning of bone resorption in diseases periodontal.
Degradation of collagen in alveolar bone destruction also lead to degradation of the
collagen pyridinoline crosslink. Pyridinoline crosslink would be released and out to the
blood vessels, then going out through urine, saliva and GCF. Pyridinoline crosslink were
consists of ICTP, pyridinoline, deoxypyridinoline, and INTP. Product degradation of
pyridinoline crosslink would not be re-metabolized. This showed that the product
degradation of collagen type I pyridinoline crosslink was specific to detect alveolar bone
destruction [2]. The conclusion is pyridinoline can be used as biomarker for detecting
alveolar bone destruction.

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