Accepted Manuscript

The multiple functions and mechanisms of osteopontin

Mehmet Arif İçer, Makbule Gezmen-Karadağ

PII: S0009-9120(18)30383-7
DOI: doi:10.1016/j.clinbiochem.2018.07.003
Reference: CLB 9817
To appear in: Clinical Biochemistry
Received date: 12 April 2018
Revised date: 3 July 2018
Accepted date: 8 July 2018

Please cite this article as: Mehmet Arif İçer, Makbule Gezmen-Karadağ , The multiple
functions and mechanisms of osteopontin. Clb (2018), doi:10.1016/
j.clinbiochem.2018.07.003

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The Multiple Functions and Mechanisms of Osteopontin

Mehmet Arif İçer1, Makbule Gezmen-Karadağ1

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Gazi University, Faculty of Health Sciences, Nutrition and Dietetics Department, 06500

Beşevler /ANKARA, TURKEY

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Corresponding Author: Mehmet Arif İÇER, Research Assistant, Gazi University, Faculty of
Health Sciences, Nutrition and Dietetics Department, Ankara/Turkey, e-mail:

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m.arif.icer@gmail.com, GSM: +905074759248

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Abstract

Osteopontin (OPN) is a highly phosphorylated glycophosphoprotein having acidic

characteristics and rich in aspartic acid. OPN, a multifunctional protein, has important

functions on cardiovascular diseases, cancer, diabetes and kidney stone diseases and in the

process of inflammation, biomineralization, cell viability and wound healing. Osteopontin

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acts on organisms by playing a key role in secretion levels of interleukin-10 (IL-10),

interleukin-12 (IL-12), interleukin-3 (IL–3), interferon-γ (IFN-γ), integrin αvB3, nuclear

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factor kappa B (NF-kB), macrophage and T cells, regulating the osteoclast function and

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affecting CD44 receptors. The aim of the present review is to address majority of different

functions of OPN protein which are known, suspected or suggested through the data obtained
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about this protein yet.
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Key words: Osteopontin, Biomarker, Medicinal biochemistry, Obesity, Cancer

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1. Introduction

Osteopontin (OPN), which is a combination of the words "osteo" meaning "bone" and

"bridge" meaning "pontin", has important roles in health [1]. OPN, the first extracellular

matrix protein identified in bone tissue by Franzén et al., is a highly phosphorylated

glycoprotein consisting of approximately 314 amino acids with a molecular weight ranging

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between 44 and 75 kDa. [2, 3].

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Osteopontin exists in a large number of tissues such as saliva, milk, bile, dentin layer of the

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tooth, kidney, brain, bone marrow, endothelial cell, smooth muscle cells, skeletal muscle cell,

mammary gland cells, chorionic villus, decidua layer of the uterus, the ganglia in inner ear,
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salivary and sudoriferous glands, bile and pancreatic tracts [4, 5]. Furthermore, OPN in the

osseous tissue is released from osteoblasts and osteoclasts acting in bone structuring.
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However, OPN expressed from osteoclasts is known to inhibit the hydroxyapatite [4] which

indicate that OPN is associated with bone destruction [6].

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Different studies have shown that OPN increases macrophages and T cells in the event of
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inflammation [4, 7]. Furthermore, there are studies suggesting that OPN suppress ectopic
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calcification and over-mineralization, and takes active roles in wound healing and preventing

renal stone formation [4, 8-10]. However, along with many studies indicating positive effects
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of OPN, some studies address negative effects of OPN such as increasing OPN release during

tumor development and metastasis and playing a key role in development of insulin resistance

by inducing the inflammation formation [11-13].

Some studies report that release of OPN is affected by some dietary factors [14, 15]. Some of

the aforesaid studies report that some foods increase OPN secretion whereas others suggest

that some foods reduce OPN secretion [14, 16].

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In the present review, OPN was examined within a wide perspective from structure and

release of OPN, positive health effects to association of negative health effects.

2. Structure and Release of Osteoprotein

Osteopontin is a highly phosphorylated glycophosphoprotein which is rich in aspartic acid

and has acidic characteristics consisting of 300 amino acids and including O-linked and N-

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linked oligosaccharides [17]. Structural form of OPN is shown in Figure 1.

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It is accepted that OPN has an arginine-glycine-aspartic acid binding zone, 2 heparin binding

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zones, one thrombin binding zone and one calcium binding zone. Moreover, matrix

metalloprotease 3 and 7 (MMP-3,7) are also linked to OPN. Osteopontin has two terminal
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zones including N-terminal and C-terminal. C-terminal binds two heparin molecules as well
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as CD44 variants whereas N-terminal includes integrin receptor binding zones [18].

Although modulation mechanism of OPN release is not fully clarified yet, release levels are
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reported to be different in different cell types [4, 19]. Osteopontin release is modulated by
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many factors through different signal pathways including protein kinase C (PKC) on certain
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cell types. For instance, PKC suppress OPN release in Src -/- fibroblasts stimulated by
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epidermal growth factor [20, 21]. Moreover, increased OPN release in case of injury and

infection is associated with cytokines [20].

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Previous studies report that vitamin D, interferon stimulating elements, glucocorticoids and

alignment rich in purine may stimulate OPN release [4, 19]. Moreover, macrophages, tumor

necrosis factor-α (TNFα) and interleukin-1β (IL-1β) stimulate the transcription and release of

OPN genes [4, 19]. Coppola et al. detected in a study at cellular level that OPN release

increased in tumor cells [22].

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Thrombine Binding Zone

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MMP Binding Zone

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Figure 1. Structural form of osteopontin [17].

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3. Effects of Osteopontin on Health NU
Osteopontin takes important roles in inflammation, biomineralization, cardiovascular

diseases, cellular viability, cancer, diabetes and renal stone disease through different
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mechanisms (Figure 2).

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Biomineralization
Inflammation
Modulation of
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Increase in macrophage
osteoclast function
and T cell count
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Wound healing Cancer

Increase in macrophage Increase in cell
infiltration and TGF- β OSTEOPONTIN
migration
secretion
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Nephrolithiasis
Diabetes Prevention of Caox
crystal formation and
Increase in insulin
accumulation
resistance

Figure 2. Major biological functions of osteopontin [2, 8, 12, 13, 23, 24].
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3.1. Osteopontin and inflammation

Inflammation is a response to prevent damage of microorganisms or toxins at cellular level or

to protect the organism as a result of any injury [25]. The roles of OPN on immune cells

during inflammation and apoptosis processes were shown in Figure 3. OPN is a significant

chemical attractant for macrophages and T cells and many researches were carried out on role

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of this substance during inflammation [4, 7, 26]. An increase in OPN release is reported from

macrophages, activated T cells, epithelial and endothelial cells as well as smooth muscle cells

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during inflammation process. However, OPN takes a role in increase of macrophage and T

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cells on inflammation areas [4, 7]. Moreover, obesity which is characterized by low grade

inflammation in adipose tissue, abnormal production of cytokines and macrophage infiltration

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is reported to increase OPN concentration both in the plasma and adipose tissue [27-29].
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There are many studies focusing on the roles of OPN glycoproteins during inflammation

process.
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It was reported that severity of herpex simplex, Mycobacterium bovis BCG and listeria
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monocytogenes-induced infections increase in tissues of OPN-null mice [7, 26]. A study

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conducted on human found out that osteopontin gene expression in human pulmonary
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macrophages increase after infection with virulent Mycobacterium bovis BCG [30]. This case

is associated with direct suppression of macrophage production through increased interleukin-

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10 (IL-10), decreased interleukin-12 (IL-12), interleukin-3 (IL–3) and interferon-γ (IFN-γ) [7,

26]. Another study conducted on humans found out that OPN resisted myobacterial infections

and diseases [31]. Isumi et al. (2015) evaluated serum OPN levels in the patients with

rheumatoid arthritis and detected statistically significant and lower OPN levels after a 1-year

treatment carried out successfully when compared with the period before treatment [32].

Schaller et al. (2009) evaluated plasma OPN levels of 31 obese patients before and after
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development of inflammation concomitant to bariatric surgery and concluded that the

postoperative inflammation causes an increase in plasma OPN levels [29]. However, possible

absorption disorders following a major procedure like bariatric surgery may affect plasma

OPN concentrations.

It may be considered due to the aforesaid roles that OPN may increase the inflammation in

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acute and chronic inflammatory diseases [4, 26, 31].

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Figure 3. Role of osteopontin on immune cells during inflammation and apoptosis [33].

3.2 Osteopontin and biomineralization

As mentioned before, OPN is released in mineralized tissues including bones and teeth and

produced by osteoclastic and osteoblastic cells at high levels [20, 34]. Osteopontin synthesis

stimulation is performed by calcitriol which is known as trigger of bone destruction [35].

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Furthermore, OPN which is one of the most strongly linked non-collagen proteins is

considered to assist binding of the osteoclasts onto the bone surface [35, 36]. Due to the

effects mentioned above, OPN has 3 major functions during biomineralization phase

including modulation of adherence of osseous cells, modulation of osteoclastic function and

modulation of matrix mineralization.

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Osteopontin increases the adhesion of bone cells by concentrating in mineralized collagen

matrix during formation of the bone tissue [8, 37]. Furthermore, OPN increases adhesion of

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osteoblast and osteoclast cells [8, 20]. However, there was not any kind of abnormality on

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bone and tooth development processes of the rats in the studies conducted on the OPN-null
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mutant rats [38, 39]. These studies pointed out that other bone matrix proteins such as osseous

sialoprotein or fibronection would perform the adherence and signal functions required for
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osseous cells [8].

Osteopontin takes a role in bone tissue destruction by two basic mechanisms. The first one is
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providing identification and adherence of osteoclastic cells by integrin αvβ3-mediated OPN;

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and the second is modulation of osteoclastic function via integrin αvβ3 [35, 36, 40].

Moreover, it is reported that OPN acts as a physical limiter limiting crystal formation in bones
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and teeth [8].

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In line with such data, OPN which has a significant importance [8, 9] in suppression of over-

mineralization may be considered to reduce the risk of bone fractures through the aforesaid

mechanisms.
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3.3 Osteopontin and cardiovascular diseases

It is stated that OPN, identified for the first time by Gihemlli et al. in the arterial tissue, may

play significant roles in development of atherosclerosis [41, 42]. Although the mechanisms of

OPN related to cardiovascular diseases are not clear, different possible mechanisms exist. One

of these possible mechanisms is OPN increasing the risk of atherosclerosis by increasing

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endothelial cell migration via αvβ3 ligand. Other possible mechanisms include OPN leading

vascular inflammation by increasing macrophage activation and release of other cytokines or

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leading development of atherosclerosis by increasing calcification in arteries [42, 43].

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Glucose-dependent insulinotropic polypeptide (GIP) which is including effects on the
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cardiovascular system is the main incretin hormones secreted by the intestine after a meal to

stimulate insulin secretion [44]. It is also reported that GIP promotes OPN expression in
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pancreatic β-cells and thus has a proliferative and antiapoptotic role in this tissue [45].

Interestingly, a single nucleotide polymorphism (SNP) (rs1800437) in the GIPR gene has
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been associated with the features of CVD [46]. In a study conducted by Berglund et al. (2015)
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a strong association between OPN and GIP hormone was found in patients with advanced

atherosclerotic disease [47]. It is also stated that incretin hormone GIP may increase
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cardiovascular disease risk by increasing OPN release in arteries [45, 47, 48].
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Vascular calcification, one of the most significant signs of atherosclerosis, is a common

condition detected in the patients with coronary artery diseases. Furthermore, vascular

calcification is known to be associated with increased risk for myocardial infarction [49].

Many studies state that OPN increases risk of atherosclerotic plaque formation leading to

calcification in arteries [50, 51].

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Dimitrow et al. (2011) implemented atorvastatin treatment (20 mg/day) on 33 individuals with

heart disease for four weeks and examined the effect of atorvastatin treatment on calcification

biomarkers. A statistically significant decrease in OPN levels as a calcification biomarker was

detected following atorvastatin treatment (p<0,05) [52]. In a study where the researchers

evaluated the mineralization developed on smooth muscles of cattle aorta, arterial

calcification was associated with release of OPN [42]. Abdalrhim et al. (2016) concluded in

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their study that increased plasma levels of OPN which has important roles in calcifications

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and inflammatory processes is associated with coronary artery disease [51]. Another study

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found higher OPN levels in cardiac valves with calcification when compared with not-

calcified cardiac valves [53]. In accordance with these data, it may be considered to use OPN
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level to detect existence and severity of coronary artery diseases.
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3.4. Osteopontin and wound healing-cell vitality

Osteopontin plays important roles in wound healing due to its effects on cell viability. Also
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some studies suggest that OPN takes these roles through different possible mechanisms. One
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of these mechanisms is protection of endothelial cells by OPN against continuous apoptosis

by increasing the nuclear factor kappa B (NF-kB) via binding to integrin αvB3 [4]. Another
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possible mechanism is active role of OPN stimulating IL-3 (Interleukin-3) and GM-CSF
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(granulocyte-macrophage colony-stimulating factor) receptors on cell vitality by binding to

CD44 which is a cell surface receptor. In addition, it is known that OPN increase release of

osteoprotegenin (OPG) by increasing NF-kB activation in endothelial cells [54].

Osteoprotegenin protein is known as a suppressor of apoptosis [54, 55]. Along with the

effects on cell vitality, OPN is suggested to have important roles in wound healing by

modulating secretion of metalloproteinase (MMP) and leveraging the fibroblast proliferation

dependent to the growth factor [4]. Furthermore, healing effect of OPN secreted with high
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levels by tissue macrophages is reported by affecting differentiation and mineralization of

osteoblasts [56]. The studies evaluating effects of OPN on wound healing were generally

carried out on the rats and focused on its effects on cell viability.

Lin et al. (2000) concluded in their study conducted at cell level that OPN increase the cell

vitality level by binding to CD44 receptor [57]. In another study performed on rats with renal

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damage, effect of OPN level was evaluated on cell vitality in kidney tissue. As a result, the

rats with lower OPN levels were found to have less cell vitality [23]. Miyazaki et al. (2008)

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evaluated the effects of OPN on corneal wound healing through comparison of the OPN-

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removed rats with the control group. It was concluded in the aforesaid study that decreased

release of myofibroblasts as well as growth factor β1 cause a delay in wound healing in OPN-
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removed rats when compared with the control group. More experimental studies are needed
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to clarify the mechanism of action of OPN, which is involved in the regeneration, release and

differentiation of fibroblasts and myofibroblasts, as well as their cell viability and wound
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healing [58].
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3.5. Osteopontin and cancer

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OPN produced by many species including human being is a multi-functional protein released

by many cells such as tumor cells and macrophages [12]. There are different studies
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conducted on humans and animals reporting that release of OPN increases in tumor

development and metastases [59, 60]. In majority of these studies, increase in OPN release in

breast, gastric, lung, prostate, liver and colon cancers is associated with tumor development,

progression and/or metastasis [12, 59, 60]. In line with these studies, use of OPN level

analysis is considered to measure metastasis potential of some tumors [11, 12].

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Osteopontin takes an important role in tumor development by leading to cell migration in

extracellular matrix [11]. However, OPN is considered to cause tumor progression by

affecting the receptors of different integrin and CD44 [11]. Furthermore, it is reported that

increase in OPN release progresses parallel to severity of helicobacter pylori infection, which

is one of the most important causes for gastric cancer [61, 62]. The role of OPN in gastric

cancer formation has not been explored as yet. Considering OPN to enhance the cell survival

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and proliferation, it may also play important roles in the helicobacter pylori-related

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precancerous changes [62]. Another possible mechanism is that increased expression of BCR-

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ABL1 gene increases OPN release in case of chronic myeloid leukemia [63]. Many other

studies focus on the correlation between OPN secretion level and development, progression
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and/or metastasis of tumor in different cancer types.
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Many studies report that OPN expression takes important roles in different possible

mechanisms of action in different cancer types (Table 1). Chang et al. (2011) performed a
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study on 105 patients infected with helicobacter pylori (42 patients with intestinal metaplasia
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(IM) and 63 patients without IM) and 29 healthy individuals; and found out that gastric OPN
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release of the patient group was statistically and significantly higher than the healthy group
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[62]. Different studies suggested that increase in OPN release is effective on prognosis of the

gastric cancer through phosphoinositide 3-kinase (PI3K)/AKT pathway, activator of

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transcription 1 (STAT1) and pro-inflammatory immune response [64, 65]. Chagan-Yasutan et

al. (2011) reported a statistically significant positive correlation between plasma OPN and

CD44 levels and the disease severity in their study carried out on 27 adults with T cell

leukemia and 30 healthy individuals [66]. Furthermore, it was detected that expression of

OPN increase in acute myeloid leukemia and chronic myeloid leukemia [63, 67]. Psyrri et al.

performed a retrospective study on 1681 patients with early stage breast cancer and showed a

negative correlation between survival rates of the individuals with breast cancer and high
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OPN mRNA expression. Moreover, the aforesaid study concluded that OPN might be used as

a biomarker in breast cancer [68].

In consideration of the study results, release of OPN which increases in some cancer types

may be used as a clinical biological marker for diagnosis and monitoring of cancer [11, 12,

60]. However, the molecular mechanism defining the role of OPN has not been clarified yet

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and it is necessary to further clarify multifactorial mechanisms of action of OPN so that it can

be used for cancer follow-up and diagnosis [12].

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Table 1 Expression of osteopontin in different cancer types

Cancerous Method Pathophysiological Mechanism Reference

tissue
Ostepontin, E-cadherin, b-catenin and Highly release of OPN appears by the
Gastric cyclooxygenase 2 expression analyses gastric tumor tissue. It was reported [69]
were performed on 346 gastric tumor that highly released OPN affect
tissues by immunohistochemistry adherence and migration of cancer
method. cells.

Plasma OPN levels were measured in A statistically significant positive

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T cell 27 adults with T cell leukemia and 30 correlation was reported between [66]
healthy individuals. plasma OPN and CD44 levels and
disease severity.

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Prostate biopsy was performed on 40 OPN was over expressed in prostate
Prostate patients with prostate cancer and 30 cancer. This was considered that OPN [70]

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patients with benign prostate may be used as an important biomarker
hyperplasia; and anti-OPN antibodies for diagnosis and prognosis of prostate
were analyzed through cancer.
immunohistochemical staining test.
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Furthermore, serum levels of OPN
isoforms and total prostate specific
antigen were measured.
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OPN concentrations as well as Lower plasma OPN levels were found

Lung plasminogen activator inhibitor-1 (PAI- associated with recovered clinical [71]
1) and vascular endothelial growth outcomes in treatment of the llung
factor (VEGF) concentrations were cancer. Survival rates of the patients
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measured through enzyme-linked with lower OPN levels are higher in

immunosorbent assay. general.
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Serum and plasma samples were The patients presenting metastases

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Rectal obtained from the patients with rectal have higher OPN release levels both [72]
carcinoma carcinoma before and after before and after chemotherapy when
chemotherapy; and some analyses were compared with the patients without
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executed through IL-6 ELISA kit, metastasis. Detection of OPN levels

ostepontin ELISA kit and may be used to determine metastasis
Immunohistochemistry method. development risk in the patients with
rectal cancer.
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OPN levels of 30 patient with ovarian
Ovarian endothelial cancer were measured
through PCR method.
An analysis was performed through
Colorectal biopsy from 64 patients with colorectal
cancer including 20 patients with
metastasis (liver) and 44 patients
without any metastasis for evaluation
of OPN release according to metastasis
state of the patients with colorectal
cancer.
OPN release was found higher in the
patients with advanced stage of ovarian [73]
cancer when compared with early-stage
cancer patients.
OPN release level of the patients with
liver metastasis was detected higher [74]
than the patients without any
metastasis.
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3.6. Osteopontin and diabetes

It is reported that OPN is also active in formation of atherosclerotic plaque including diabetic

vascular complications [13, 75]. Osteopontin is highly secreted on medial layers of diabetic

rats and patient arteries [76]. Furthermore, as mentioned before, pro-inflammatory cytokines

which have a significant importance in development of diabetic complications increase in line

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with release of OPN [75]. Consequently, it is reported that OPN may play a key role in

development of insulin resistance by increasing macrophage accumulation in adipose tissue

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and promoting the inflammation formation [13]. Moreover, it is reported OPN level increases

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on vascular wall of diabetic individuals; and this may cause cell growth by increasing the
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OPN release [76]. It has also been reported that hyperglycemia stimulates OPN gene

expression in mesangial cells [77, 78]. However, it is not yet clear which mechanisms
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hyperglycemia enhances OPN gene expression, which is related to similar epigenetic

mechanisms described for NF- kB in blood vessels [79]. Hyperglycemia, a potent activator of
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histone acetylation and methylation, has been reported to increase the expression of OPN
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gene by increasing the activation of histone marks H3K9ac, H3K4me1 and H3K4me3 [80].
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In addition to these mechanisms, it is noted that OPN has many similar effects with GIP,
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including the regulation of adipocyte metabolism in fat tissue [13, 81] and the effect on

survival rates of β-cells in pancreatic islets [82, 83]. The incretin hormone GIP promotes
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pancreatic β-cell function by potentiating insulin secretion and β-cell proliferation [45]. GIP, a

potent stimulator of adipogenesis, is thought to cause insulin resistance by increasing OPN

release in the adipose tissue [84].

A study performed on the rats suggested that release of OPN was more in the rats with

diabetic nephropathy when compared with the control group [85]. Another study conducted
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on the rats concluded that the decrease in OPN level created an improvement in insulin

resistance [13]. In the study carried out by Daniele et al. (2014) on the patients with Type 2

diabetes as well as healthy individuals, it was detected that plasma OPN levels of the patients

with Type 2 diabetes were higher than the control group. Another outcome of such study was

the correlation between plasma OPN level and tumor necrosis factor-α (TNF-α) secretion

which mediate obesity-induced insulin resistance [86]. Nakamachi et al. found out in their

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study that proliferation-activated receptor (PPAR)α ligands suppressed expression of OPN in

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the individuals with Type 2 diabetes. Various studies report that OPN release increase in

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diabetes [87-89]. Gordin et al. (2014) carried out a study on the patients with Type 1 diabetes

and detected serum OPN is a strong predictor of incipient diabetic nephropathy. This study
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also suggests that serum OPN may be of clinical significance for the risk prediction of CVD

events in patients with Type 1 diabetes [90].

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In consideration of outcomes of the previous studies, it may be concluded that decreased

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plasma levels of OPN concentrations may take an important role in prevention of diabetic
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complications; however more comprehensive studies are needed [13, 75].

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3.7. Osteopontin and kidney stones

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Osteopontin is a protein which is synthesized from kidneys and released into the urine
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through epithelial cells and has important functions in formation of kidney stones [10, 91]. In

normal urine, magnesium tend to be crystallized through supersaturation in insufficient levels

of inhibitor molecules such as pyrophosphate and citrate [4]. Along with the effect of inhibitor

molecules on inhibition, they actually act through different proteins in the urine [4, 92]. Many

different studies report that OPN, as one of the aforesaid molecules, inhibit formation, growth

and accumulation of CaOx crystals [10, 93, 94]. In addition, OPN is reported to show an anti-
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lithogenic effect by inhibiting adherence of the crystals onto the renal epithelial cells [95].

However, there are different studies suggesting that OPN increases the risk of CaOx stone

formation by increasing renal tubular cell damage and crystal adherence onto the epithelium

[95-98].

Osteopontin is secreted from renal epithelial cells including loop of henle, distal tubular cells

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and papillary epithelial cells [4]. A negative correlation was found between urinary OPN level

and stone formation in different studies [24, 99]. Furthermore, kidney stones consists of

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proteins with a great amount. OPN is mentioned as one of the most important proteins within

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structure of calcium oxalate and calcium phosphate stones [100, 101]. Two basic mechanisms
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explain significantly lower OPN levels in the urine of the patients with kidney stone; the

hypothesis that lower levels of OPN which prevents formation, enlargement and accumulation
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of CaOx crystals or the hypthesis that OPN synthesis continues but less extraction in urine

because existing in the stone formation [10, 91, 92]. The second hypothesis is accepted more,
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since it is known that expression of OPN increases in the patients whos kidney stones was
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created experimentally and OPN strictly bind to hydroxyapetite [92, 102].

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There are studies focusing on genetic modifications on the OPN gene [103, 104]. Majority of
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these genetic studies address the polymorphisms on OPN gene [24, 104]. Liu et al. (2010)
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conducted a study on 249 patients with calcium stones and 247 healthy individuals and

detected -156 delG/G polymoprhism of the OPN gene significantly higher (p=0,037) in the

patient group. The aforesaid study concluded that such gene polymorphism level would be

used as a method to detect formation of calcium stones [24].

In a study carried out with 111 patients diagnosed with urinary system stone disease including

83 males and 28 females with an age range of 20 to 66 years, urinary OPN excretion of the
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patient group for 24 hours as well as the ratio to creatinine was found to be lower than the

control group (p<0.01) [99]. Another study evaluated urinary OPN excretion on 249 patients

with kidney stone as well as 247 healthy individuals. The study reported that urinary

excretion of OPN was significantly lower than the control group (p<0.001) [24]. On the other

hand, Tsuji et al. (2007) did not detect significant difference between urine OPN levels of the

participants in the study conducted on 120 patients with calcium oxalate stone and 40 healthy

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individuals (p>0,05) [105]. In line with such data, use of urinary OPN level may be

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considered as a biochemical parameter to diagnose the risk of stone formation. However,

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more human studies and reduction of measurement costs by new methods should be

performed for routine implementation.

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4. Conclusion
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OPN, which can be secreted by many tissues, has many controversial effects on health. It may

be considered that OPN increases the inflammation in acute and chronic inflammatory
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diseases due to its roles in increase of macrophage and T cells in inflammation sites.
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Furthermore, it may be concluded that OPN may reduce the risk of bone fractures by

modulating the adherence of osseous cells and matrix mineralization. Although the
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mechanisms are not clear yet, one of positive effects of OPN on health is anti-lithogenic
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effect. However, increased levels of OPN have some negative effects along with positive

effects on health. Some negative effects include that OPN stands as a risk factor for

cardiovascular diseases, diabetes and cancer. Along with the data presented, use of OPN level

may be considered as a new biochemical parameter to determine the risk of cardiovascular

diseases, diabetes and cancer. However, more human studies and reduction of measurement

costs by new methods should be performed for routine implementation.

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Conflict of interest

The authors have no relevant interests to declare.

Acknowledgment

Funding/support. No external funds supported this work.

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Highlights

 Osteopontin is a significant chemical attractant for macrophages and T cells.

 Osteopontin reduce the risk of bone fractures through the different mechanisms.

 Osteopontin increases risk of atherosclerotic plaque formation leading to calcification

in arteries.

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 Plasma osteopontin levels correlate with tumor necrosis factor-α (TNF-α) secretion.

 Osteopontin plays important roles in wound healing due to its effects on cell viability.

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 Use of urinary osteopontin level may be considered as a biochemical parameter to

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diagnose the risk of stone formation. NU
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