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 Table of Contents  
Year : 2019  |  Volume : 16  |  Issue : 1  |  Page : 33-39

The insulin-like growth factor binding protein-3/transferrin axis in pathogenesis of oral lichen planus and as a salivary biomarker for disease activity

1 Department of Oral Medicine, Diagnosis, Periodontology and Radiology, Faculty of Dental Medicine, Al Azhar University (Girls Branch), Cairo; Department of Oral Medicine, Diagnosis, Periodontology, Faculty of Dentistry, MSA University, Giza, Egypt
2 Department of Oral Medicine, Diagnosis and Periodontology, Faculty of Dentistry, The British University in Egypt (BUE), Cairo, Egypt
3 Department of Oral Medicine, Periodontology and Diagnosis, Faculty of Dentistry, Bader University, Cairo, Egypt
4 Department of Biochemistry, Faculty of Medicine, Cairo University, Cairo, Egypt

Date of Submission17-Sep-2018
Date of Acceptance23-Nov-2018
Date of Web Publication13-Jun-2019

Correspondence Address:
Naglaa M El-Wakeel
ElkhamayelCompound, Elsheikh Zayed, 6October, Giza
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/tdj.tdj_33_18

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Insulin-like growth factor binding protein-3 (IGFBP-3) has been linked to the pathology of multiple inflammatory diseases of immunological background. Till now, no data is available on the involvement of IGFBP-3 in oral lichen planus (OLP) pathogenesis. Thus we aimed to gather preliminary data concerning salivary levels of IGFBP-3 and its binding protein transferrin (Tf) in patients suffering from OLP compared to normal controls and correlate it with clinical picture, this is to investigate: (a) a possible role in pathogenesis and (b) its validity as a biomarker for disease activity.
Patients and methods
Salivary samples from 40 patients suffering from OLP (clinically evaluated using REU scoring system) and 40 controls were collected and Tf and IGFBP-3 levels were estimated using enzyme-linked immunosorbent assay, for statistical analysis, analysis of variance followed by Turkey's post hoc and Pearson's correlation tests were used.
Significantly higher salivary levels of IGFBP-3 and Tf (2533.45 ± 290.35 and 13.91 ± 2.23 ng/ml, respectively) were recorded in OLP compared to controls (1215.3 ± 428.92 and 3.33 ± 0.24 ng/ml, respectively, P < 0.0001). A positive correlation between IGFBP-3 and Tf levels with REU in OLP was detected.
Our data suggests that IGFBP-3 and Tf seem to play a role in pathogenesis of OLP and could be considered as a reliable marker in monitoring disease activity. However, further studies are required to further elucidate the role of the TGFBP-3/Tf binding system in the pathogenesis of OLP.

Keywords: insulin-like growth factor binding protein-3, oral lichen planus, saliva, transferrin

How to cite this article:
El-Wakeel NM, Ghalwash DM, Gouda OM, Shaker OG. The insulin-like growth factor binding protein-3/transferrin axis in pathogenesis of oral lichen planus and as a salivary biomarker for disease activity. Tanta Dent J 2019;16:33-9

How to cite this URL:
El-Wakeel NM, Ghalwash DM, Gouda OM, Shaker OG. The insulin-like growth factor binding protein-3/transferrin axis in pathogenesis of oral lichen planus and as a salivary biomarker for disease activity. Tanta Dent J [serial online] 2019 [cited 2021 Dec 7];16:33-9. Available from: http://www.tmj.eg.net/text.asp?2019/16/1/33/260277

  Introduction Top

Oral lichen planus (OLP) is a chronic mucocutaneous disease, usually affecting middle-aged individuals with a female sex predilection. Three clinical forms of OLP are described: reticular; atrophic or erythematous; and erosive type. The reticular lesions appear as a network of connecting and overlapping lines, papules or plaques, associated with fewer symptoms[1]. The erosive and ulcerative forms are more destructive forms that cause enormous oral discomfort. Oral lesions are located primarily on the posterior buccal mucosa, bilaterally. Other affected sites are the dorsal surface of the tongue, labial mucosa, and gingiva. Up to 44% of patients with OLP develop coincident skin lesions that typically appear as pruritic, flat-topped, violaceous papules, and plaques that predominantly affect the flexor aspects of the wrists or ankles. OLP presents a significant problem to oral clinicians because of serious function disturbances affecting the quality of life, lack of permanent cure, and its unspecified malignant transformation risk[2],[3].

The etiology and pathogenesis of OLP has been the focus of many researches as it is not fully understood. Several antigen-specific and nonspecific inflammatory mechanisms have been put forward to explain the pathogenesis of the disease. Generally, OLP is considered as a T-cell mediated autoimmune disease in which cytotoxic CD8+ T-cells trigger epithelial cells apoptosis[3],[4]. As well, it is believed that a cytokine-mediated lymphocyte homing mechanism plays an important role. The inflammatory process in OLP depends upon a series of molecular stimuli originating in the inflammatory infiltrate. Some molecules and radicals generated locally can influence important cell cycle regulation mechanisms, for example, apoptosis, cell cycle arrest, and cell proliferation[5].

The insulin-like growth factor binding proteins (IGFBPs) are six high affinity proteins that bind IGF, regulating its action and bioavailability. They exhibit unique biological actions, including cell growth inhibition or promotion and induction of apoptosis. Biological functions of IGFBPs are divided into two aspects: those with IGF dependent action[6], and those with IGF-independent action, as IGFBPs can exert their own intrinsic biological roles, independent of IGFs, this includes a role in inflammation, angiogenesis, and tumorigenesis[7]. Among them, IGFBP-3 is a well documented inhibitor of cell growth and/or promoter of apoptosis in various cell types in an IGF-independent manner (IGFBP-3 DM). IGFBP-3 is mainly derived from hepatic Kupffer cells and is the most abundant in plasma. Recent studies have also shown that IGFBP-3 plays a critical role in inflammatory responses through IGF-I-dependent and/or IGFI-independent mechanisms[7],[8]. IGFBP-3 has other functional roles, such as a proangiogenic effect on endothelial precursor cells[9], IGFBP-3 contributes to the pathophysiology of a variety of human diseases including cancer, diabetes, ischemia, asthma, and Alzheimer disease[10],[11].

Circulating IGFBP-3 levels are affected by many factors, such as age, hormones, nutrition, and combined diseases. IGFBP-3 is also produced by peripheral tissues where it serves important paracrine and autocrine roles in modulating cellular growth and apoptosis, local IGFBP-3 levels are reported be induced by a variety of molecules, such as interleukin-1, tumor necrosis factor-alpha (TNF-α), and transforming growth factor (TGF)-β[11],[12].

The IGF-independent cellular effects of IGFBP-3 are mediated through specific IGFBP-3 binding proteins/receptors located at the cell membrane, cytosol, or nuclear compartments and in the extracellular matrix[13]. Transferrin (Tf) has been identified as one of the IGFBP-3 binding proteins. Tf is a plasma protein that plays a central role in transferring iron around the body to sites where it is needed. Tf synthesis and storage are regulated by iron levels and nutritional status, Tf transports Fe++ into the interior of the cell by transmembrane receptor mediated endocytosis (TfR1/TfR2) expressed on the surface of many cells[14],[15].

Tf has been implicated in growth and differentiation activities that are independent of the iron-binding role. Apo-Tf preparation have been shown to possess growth-promoting effect, over expression of the Tf receptor (CD71) has been reported in several cancers including lung, pancreas, and breast[16],[17]. However, other data showed that induction of apoptosis is one of Tf multiple effects, that has not been fully determined[18]. Recently, Tf has been linked to inflammation, evidenced by the identification of multiple Tf species in the spleen of mice with collagen-induced arthritis which is a chronic inflammatory autoimmune disease[19].

The IGFBP-3/Tf interaction is reported to be specific and sensitive, with a high association rate similar to IGF-I. The validity of IGFBP-3/Tf binding through multiple independent in-vitro methods has been confirmed, and a physiologically significant consequence of this binding on cell proliferation and apoptosis was demonstrated. It was suggested that, in addition to the modulation of IGF activity at the cell membrane and direct interactions with its own specific receptors, IGFBP-3 may also affect cell growth through several Tf-dependent and Tf-R-dependent mechanisms[12],[18].

Saliva as a media for investigation in oral diseaseshas many advantages over serum because of its direct contact with oral lesions, its contents of fallen cells plus being easily collected, less traumatic, readily available, easy to handle, cost effective, and safe[20]. Despite the critical role of IGFBP-3 in the pathophysiology of many inflammatory autoimmune diseases, yet, no data is available for its levels in OLP, furthermore, only two studies are available on salivary Tf expression, Dowling et al.[21], reported that Tf levels were significantly increased in saliva of patients with head and neck SCC compared to controls and Koc et al.[22], showed that these levels decreased significantly during radiotherapy treatment. As for Tf expression in OLP, Mattsson et al.[23], showed that tissue biopsies of chronic graft versus host disease and OLP had significantly increased number of lymphocytes with Tf receptors compared with the pretransplant and control groups.

Given that OLP is a chronic inflammatory autoimmune disease of the oral mucosa in which inflammation and epithelial cell apoptosis are hallmarks in pathogenesis, it could be hypothesized that IGFBP-3 and Tf could have a role in OLP pathogenesis, and could be a potential biomarker for disease activity evidenced by their elevated local salivary levels, especially that, serum levels of both IGFBP-3 and Tf are affected by multiple systemic factors such as age, growth hormones, and nutritional status[8],[11] and it was strongly suggested that local tissue levels of IGFBP-3 or its mRNAs may be useful as diagnostic or prognostic markers[24]. Thus, the aim of the present study was to assess levels of IGFBP-3 and Tf in saliva of patients suffering from OLP and correlate it to clinical parameters as compared to healthy controls.

  Patients and Methods Top

Study participants were 80 age-matched and sex-matched individuals, selected and enrolled after signing an informed consent. Both the protocol and consent forms were reviewed and approved by the Medical Ethical Committee of Al-Azhar University. This study was conducted according to the Declaration of Helsinki Principles and according to the principles good clinical practice. OLP patients were selected from the outpatient's clinic of the Oral Medicine Department of Al-Azhar and MSA Universities, Faculty of Dentistry, during the period of June 2015 to May 2016. The control participants were selected from visitors and staff of the faculties. All participants were subjected to an assessment protocol that included careful history review, general assessment of health. A detailed medical history of each participant was obtained according to the questionnaire of the modified Cornell Medical Index[25].

Participants groups

Participants were divided into two groups, the first group included 40 patients (17 male and 23 female; mean age, 43.83 years) suffering from OLP with multiple visible symptomatic lesions diagnosed on the basis of the clinical and pathological characterizations according to the modified WHO criteria of OLP[26], whereas group 2 included 40 healthy controls who were systemically free and not suffering from any oral or systemic illness (21 males and 19 females; mean age, 43.8 years).

Criteria of patient selection

Patients who had oral lichenoid lesions due to graft versus host disease, lupus erythematosus or hepatitis C were excluded. As well, patients with Sjőgren's syndrome or previous radiotherapy or chemotherapy to the head and neck region in the past 6 months prior to sample collection were excluded because of expected difficulty in obtaining saliva from these patients. OLP group included newly diagnosed patients, patients previously diagnosed with oral epithelial dysplasia or Oral Squamous Cell Carcinoma were excluded. Alcohol consuming patients were excluded as alcohol consumption was shown to affects levels of IFGBP-3 expression[27].

Full dermatological and oral examination that was carried out by a qualified clinician, for clinical evaluation of the OLP patients the reliable, easy to use REU scoring system was used [Table 1][28], the mouth is divided into 10 regions (lip, left cheek, right cheek, dorsal tongue, ventral tongue, floor of mouth, hard palate, soft palate, maxillary gingival, and mandibular gingival). The signs and symptoms were scored. Pain scores were not recorded as REU correlates with numerical rating scale for pain[29].
Table 1 Scores of REU signs for oral lichen planus[28]

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Salivary sample collection

Whole unstimulated saliva samples were collected early in the morning (between 6 and 9 a.m.) under resting condition in a quiet room. Patients were asked to brush their teeth and rinse their mouth with clean water before they went to sleep the day before sample collection and refrain from eating or drinking, for at least 1/2 h prior to saliva collection.

A water mouth rinse was administered prior to saliva sample collection. Each individual expectorated less than 5 ml of saliva into a sterile centrifuge tube.

Saliva sample processing

Immediately after the saliva sample was collected, it was centrifuged at 2600g for 20 min at 4°C. After centrifugation, the supernatant was separated from the pellet. Three proteinase inhibitors were added to 1 ml of the supernatant: 1 l of aprotinin (Sigma-Aldrich, St Louis, Missouri, USA) (10 mg/ml), 3 l of sodium orthovanadate (Sigma-Aldrich) (400 mmol/l), and 10 l of phenyl methyl sulfonyl fluoride (Sigma-Aldrich) (10 mg/ml). The samples were then stored at − 80°C until future use. All samples were analyzed within 6 months after the samples were collected and processed.

Detection of insulin-like growth factor binding protein-3 and transferrin level in salivary samples

The level of Tf and IGFBP-3 in saliva was measured using enzyme-linked immunosorbent assay kits, for Tf (Assaypro, St Charles, Missouri, USA), and for IGFBP-3 (Active IGFBP-3 Aviscera Bioscience Inc., Santa Clara, Canada), were used according to the manufactures instructions.

Statistical analysis

Tested values were presented as mean and SD values. Data were explored for normality using Kolmogorov–Smirnov test of normality. The results of Kolmogorov–Smirnov test indicated that most of data were normally distributed (parametric data), so analysis of variance test was used to compare between the two groups, followed by Tukey's post-hoc test, when analysis of variance revealed a significant difference. The significance level was set at P value less than or equal to 0.05. Statistical analysis was performed with statistical package for the social sciences, version 16.0 for Windows (SPSS Inc., Chicago, Illinois, USA).

  Results Top

A total of 84 saliva samples were collected during the study period. Four samples showed salivary IGFBP-3 levels below the minimum detection level and were excluded from analysis. Of OLP patients, 28 (70%) patients had only oral lesions, and 12 (30%) patients had both oral and skin lesions. In seven (17.5%) patients, skin lesions were of the classic LP type, two (5%) had actinic LP, one (2.5%) had hypertrophic LP, and two (5%) had both classic and hypertrophic LP. Common sites for oral lesions of OLP patients were buccal mucosa and gingiva/alveolar ridge area, the duration of the disease ranged from 6 months to 9 years with a history of remissions and exacerbations. Age and sex distribution of all groups are presented in [Table 2]. χ2 test revealed no significant difference in age (P = 0.0727) or sex distribution (P = 0.3372).
Table 2 Age and sex distribution in different groups

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Regarding the salivary levels of Tf and IGFBP-3, significantly higher levels were recorded in OLP compared to controls (P < 0.0001). Turkey's post hoc revealed a significant difference between the two tested groups [Table 3]
Table 3 Salivary levels of transferrin and insulin-like growth factor binding protein-3 in oral lichen planus versus controls and significance of the difference (analysis of variance test)

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Pearson's correlation test revealed a weakly positive correlation between salivary levels of Tf and IGFBP-3 levels in both tested groups [Table 4]. As well, Pearson's correlation test revealed a weakly positive correlation between Tf salivary levels and REU in OLP [Table 5], and between IGFBP-3 levels and REU [Table 6].
Table 4 Correlation between transferrin and insulin-like growth factor binding protein-3 salivary levels (Pearson's correlation test)

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Table 5 Correlation between transferrin levels and REU (Pearson's correlation test)

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Table 6 Correlation between insulin-like growth factor binding protein-3 salivary levels and REU (Pearson's correlation test)

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  Discussion Top

OLP is a chronic inflammatory autoimmune disease that frequently involves oral mucosa, molecular mechanisms underlying the inflammatory reaction, epithelial cell apoptosis, angiogenesis, and T-cell activity in OLP are not yet fully understood, as a result, no permanent cure has been developed (three IGFBP-3 exhibits clear and distinct biological effects, including inhibition of cell proliferation and induction of apoptosis in various cell types in an IGF-independent manner)[30]. IGFBP-3 has been associated with breast tumorigenesis, it was suggested that IGFBP-3 might predominantly influence tumor growth at local level owing to its direct local production by breast tumor cells[31]. That is why saliva was chosen in the present study to investigate local levels of IGFBP-3 in OLP.

The significantly elevated salivary levels of IGFBP-3 in OLP patients compared to controls (2533.45 ± 290.35 and 2533.45 ± 290.35 ng/ml, respectively), reported in our study could be explained by the growth inhibitory effects of IGFBP-3, a number of mechanisms could be put forward to justify a possible role for IGFBP-3 in pathogenesis of OLP.

Epithelial cell death by apoptosis, is a hallmark in OLP pathogenesis and is defined as proceeding through either an intrinsic pathway, initiated by intracellular stimuli such as oxidative stress or DNA damage, or an extrinsic pathway, initiated by extracellular stress signals. These mechanisms require the activation of different proteases, including caspase-8 for extrinsicapoptotic mechanism and caspase-9 for caspase-dependent intrinsic apoptosis[32]. IGFBP-3 has been demonstrated to induce apoptosis either directly or by potentiating other agents that activate the intrinsic pathway, such as chemotherapeutics and irradiation[33]. Apoptosis induced by IGFBP-3 can involve the activation of both caspase-8 and caspase-9[34]. At least two recently discovered unrelated proteins (LRP1 and TMEM219) have been designated as receptors for IGFBP-3, the latter in the presence of IGFBP-3 induces caspase-8-dependentapoptosis[35]. Caspase-8 activation has been shown to be involved in pathogenesis of OLP evidenced by its positive expression in 87% of the OLP specimens[36], further, oxidative stress that induces caspase-9 intrinsic apoptosis is a well-known event in OLP pathogenesis[3],[4]. IGFBP-3 was proven to be inducible by the tumor suppressor p53[37]. P53 was reported to be highly expressed in OLP tissues compared to normal control[38]. IGFBP-3 significantly enhances TNF-related apoptosis induced cell death by inhibiting nuclear factor-κB (NF-κB) activation[39].

In recent years, the dysregulation of autophagy-associated genes and proteins has been recognized and intensely investigated as it increases the susceptibility to diverse diseases, including inflammation, autoimmune disorders, and cancer. An intracellular strong interaction between IGFBP-3 and heat shock protein GRP78 was shown to promote autophagy[40]. Recently, dysregulation of T-cell autophagy was shown to be involved in pathogenic immune response of OLP and was correlated with clinical patterns[41].

Another possible mechanism that could explain the high expression of IGFBP-3 in saliva of OLP and at the same time can point to a possible role in malignant transformation of OLP is that IGFBP-3 could activate Smad2 and Smad3 phosphorylation[42], one step in malignant development is epithelial mesenchymal transition, induced by TGF-β, which uses the Smad proteins as mediators for its signaling. Significantly higher expression of Smad3 in OLP compared to normal oral mucosa was recently reported[43]. Moreover, TGF-βI expression was significantly higher in OLP carcinogenesis patients than in OLP ones[44]. While the other observation demonstrated that the inhibition of the TGF-β/Smad pathway may contribute to the proliferation of keratinocytes in erythematous OLP[45]. Finally, local production of IGFBP-3 was proven to be induced by TNF-α, which is the key inflammatory mediator in OLP pathogenesis[46].

Tf and Tf-R plays a crucial role in the cellular uptake of iron that is essential for the growing cells as DNA synthesis, electron transport, and mutagenic signaling pathways are iron dependent processes, thus, Tf and Tf-R have been proven to be over expressed in OSSC and oral dysplasia[47]. On the other hand, Tf was shown to perform other actions independent of its iron-binding role, induction of apoptosis are among these actions[18]. The present study demonstrated a significant rise in Tf levels in saliva of OLP patients compared to controls (13.91 ± 2.23 and 3.33 ± 0.24 ng/ml, respectively), Tf has been found to play an important role in T-cell activation and proliferation, in development of T-cell driven experimental autoimmune encephalomyelitis, Saksida et al.[48] proved that Tf exerted immunomodulatory effects on T cells by down regulating IL-2 in CD3+ T cells, IL-2 is a key growth and death factor for antigen-activated T lymphocytes and is essential for maintenance of self-tolerance[49]. With the lack of sufficient data about the possible role of Tf in pathogenesis if OLP, the previous scenario of Tf effect on T cells and IL-2 could be applied as a hypothesis in pathogenesis of OLP, but indeed further studies are needed.

Like IGFBP-3, the pro-apoptotic effect of Tf could cause its elevated levels in saliva of OLP patients. In a subpopulation of marrow mononuclear cells expressing CD56 (NK cells), Tf caused enhanced apoptosis[18]. Tf has been found to activate apoptosis through the production of reactive oxygen species and activation of transcription of NF-κB[50]. Recently, NF-κB-dependent cytokines and pro-inflammatory mediators were detected in higher levels in the saliva and serum from patients with OLP. Further, nuclear expression of NF-κB were higher in the OLP lesions[51]. In the present study and maybe because of the small sample size, a week positive relation was reported between the two tested proteins and REU.

It was previously reported that both IGFBP-3 and Tf stimulated sheep bladder smooth-muscle cell growth, but that their combination inhibited growth, hence, it was suggested that the IGFBP-3/Tf complex might be able to inhibit endogenously produced IGF-II, that was shown to be made in these cells[13]. IGFBP-3 was suggested to affect cell growth through several Tf-dependent mechanisms, and that Tf/IGFBP-3 binding may directly interfere with each ligand from binding its own natural receptor, depending on the iron or nutritional status of the tissue or organism, in this context, it worth mentioning that OLP has been associated with decreased serum iron levels[52]. Whether these Tf/IGFBP-3 interactions occur predominantly at the cell surface or in the cytosolic or nuclear compartments is unknown, and further IGFBP-3 binding proteins remain to be discovered. Results of the present study suggests that IGFBP-3 and Tf could be considered to play a role in the pathogenesis of OLP but due to the pleiotropic nature of IGFBP-3 and Tf activity, further investigations are required to determine the subcellular localization of both proteins, different mechanisms and molecules involved in such process.

  Conclusion Top

Our preliminary results demonstrated that IGbP-3 and Tf levels are significantly elevated in saliva of OLP, with a positive correlation between these levels and clinical features suggesting that both proteins could play a role in the pathogenesis of OLP plus being a reliable marker for disease activity, but further biochemical and cellular localization studies are required.


The authors greatly appreciate the statistical assistance of Dalia Elrouby, Professor of Oral pathology, Faculty of Oral and Dental Medicine, Cairo University, Cairo, Egypt.

N.M.E. designed the study and wrote the manuscript, O.G.S. did the biochemical analysis, D.M.G. and O.M.G. collected the samples, did the clinical examinations and took part in writing the manuscript.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]


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