Possible salivary and serum biomarkers for oral lichen planus A Totan1, D Miricescu1, I Parlatescu2, M Mohora1, M Greabu1 1Biochemistry

Department, and 2Oral Pathology Department, Faculty of Dental Medicine, University of Medicine Carol Davila, Bucharest, Romania

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Accepted February 3, 2015

Abstract There are few reports concerning the potential for clinical application of oxidative stress (OS) and collagen degradation markers in oral lichen planus (OLP) patients. We investigated the possibility of using some disease-related biomarkers in saliva and serum of OLP patients. Our study included 30 patients with OLP and 30 controls. We evaluated serum and salivary OS biomarkers including 8-OHdG, MDA, uric acid, TAC and GPx. We also investigated collagen degradation markers such as CTX I and MMP-8. We found significantly increased salivary levels of MMP-8 and CTX I in the OLP group compared to controls and significant differences between the OLP and control groups in serum and saliva for 8-OHdG, MDA (significantly increased), uric acid, TAC and GPx (significantly reduced). Currently there are no criteria for evaluating which OLP patients have a greater risk of malignant transformation. In addition to clinical surveillance, the serum and salivary biomarkers that we evaluated may be useful biomarkers for monitoring OLP patients in the future. Key words:  oral lichen planus, oxidative stress, saliva

Oral lichen planus (OLP) is a chronic oral inflammatory disease of mysterious etiology that is characterized by abnormal epithelial keratinization and T-cell mediated chronic immune response (Ismail et  al. 2007). Clinically, OLP appears more frequently in the classic reticular form as a result of coalescence of papules and may be asymptomatic or may cause mild discomfort. The most painful OLP manifestations are characterized by erythema, erosions and ulceration. If the lesions become chronic, they may become either hyperplastic or atrophic (Gonzalez-Moles et al. 2008). Histological examination of OLP reveals dense inflammatory infiltrate in the lamina propria, consisting mainly of T-cells, liquefaction and degeneration of basal keratinocytes and basal membrane, and hyperkeratosis or atrophy

Correspondence: D. Miricescu, Biochemistry Department, Faculty of Dental Medicine, University of Medicine Carol Davila, Bucharest, Romania. E-mail: [email protected] © 2015 The Biological Stain Commission Biotechnic & Histochemistry 2015, Early Online: 1–7.

DOI: 10.3109/10520295.2015.1016115

of the keratin layer (Van der Meij and Van der Waal 2003, Dorrego et  al. 2002, Sugerman et  al. 2002). OLP pathogenesis is complex and possibly involves antigen presentation by the oral keratinocytes that could be of either exogenous or endogenous origin (Farhi and Dupin 2010, Lodi et al. 2005). Officially, the World Health Organization (WHO) classifies OLP as a potentially malignant disorder and suggests that OLP patients should be monitored closely (Warnakulasuriya et  al. 2007). The severe erosive form of OLP appears to have the highest risk of malignant transformation (Barnard et  al. 1993). The current hypothesis for possible malignant transformation is that chronic inflammation plays an important role in carcinogenesis. Increased cytokines and growth factors can facilitate oral carcinogenesis (Kawanishi et al. 2006). Reactive oxygen species (ROS) play a key role in inflammation-mediated carcinogenesis (Kaufman and Lamster 2002). Excess production of ROS during a neutrophil respiratory burst can cause DNA damage, protein and lipid oxidation, and 1

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antioxidation defense system imbalance (Valavanidis et  al. 2009). Antioxidants are present in all body fluids including saliva and help provide protection against damage caused by ROS (Tamaki et al. 2008). ROS produced in oral cavity can diffuse into the systemic circulation. Increased circulating ROS together with decreased antioxidant levels may affect overall health negatively (Battino et al. 1999, Ergun et al. 2011). Saliva is the principal fluid responsible for protection of the oral cavity from antioxidants. The salivary antioxidant system includes uric acid and GPx (Battino et al. 1999, Ergun et al. 2011). The use of saliva for serum analysis has obvious advantages including easy access and non-invasive collection. Therefore, saliva may be the basis for a cost-effective approach for disease monitoring and screening of large populations (Kaufman and Lamster 2002). There are few reports concerning the use of saliva, serum ROS and collagen degradation markers in OLP patients for clinical application. Consequently, we investigated the possibility of detecting some disease-related biomarkers including 8-OHdG, MDA, uric acid, TAC, GPx, CTX I and MMP-8 in saliva and serum of OLP patients.

Material and methods Patients All clinical oral examinations were performed at the Oral Pathology Department, Faculty of Dental Medicine, UMF Carol Davila, Bucharest. Our study was approved by the local Ethical Committee and written informed consent was obtained from all participants. OLP diagnosis was established by the presence of characteristic clinical lesions: largely symmetrical bilateral reticular lesions with liquefaction degeneration of the basal epithelial layer and subepithelial band-like inflammatory infiltrate in biopsy tissue samples. Patients under drug treatment or presenting with epithelial dysplasia or clinical/histological signs of oral squamous cell cancer at the time of OLP diagnosis were excluded from the study. We also excluded from our study patients with gout (serum uric acid levels  7.2 mg/dl), hepatic disease, renal disease, diabetes or metabolic syndrome. Thirty nonsmoking patients with OLP (15 males, 15 females) 18  68 years old constituted the OLP group. Thirty nonsmoking healthy individuals (20 males, 10 females) in the same age range as the OLP patients constituted the control group. Gender has not been reported

to influence salivary levels of 8-OHdG, MDA, uric acid, TAC, GPx, CTX I and MMP-8 in OLP patients (Aqha-Hosseini et al. 2012). Normal appearing samples of oral mucosa were obtained by biopsy from all control subjects and OLP patients. The following data were collected from patients with OLP: age, sex, age of lesions (grouped as  6 months, 6  12 months and  12 months) and presence or absence of classic clinical symptoms of OLP. An oral examination was performed to distinguish reticular lesions with white striae from atrophic/erosive lesions accompanied by bilateral reticular lesions. The anatomical localization of the lesions also was recorded. All biopsy samples (OLP and controls) were examined using hematoxylin and eosin staining to assess the intensity of the subepithelial inflammatory infiltrate and basal epithelial layer liquefaction using the criteria of Bloor (Bloor et al. 1999). Saliva and blood collection Samples of saliva were obtained in the morning between 9 and 10 AM and subjects were asked not to eat, brush their teeth or use mouth rinse for at least 2 h prior to sample collection. We collected 1.0  2.0 ml of unstimulated saliva in a sterile test tube. After collection, saliva samples immediately were centrifuged for 10 min at 800 x g to remove bacterial and cellular debris. All determinations were performed using the supernatant. During the same morning, we collected 5 ml of blood from the fasting control and OLP patients and the serum was obtained immediately by centrifugation. Salivary and serum uric acid, albumin, TAC and GPx were measured immediately after sample collection. For 8-HOdG, MDA, MMP-8 and CTX, salivary and serum samples were frozen at 280° C until assayed. Sample analysis The concentrations of all salivary substances were expressed relative to the salivary concentration of albumin (uric acid, mg/mg albumin; TAC, mmol/mg albumin; MDA, nmol/mg albumin; 8-OHdG, ng/mg albumin; GPx, U/mg albumin; MMP-8, ng/mg albumin; CTX I, ng/mg albumin) to avoid the influence of salivary flow. Salivary and serum albumin were measured by the bromocresol green method using a kit from Biosystems (Barcelona, Spain) according to the supplier’s instructions.

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Lipid oxidation The MDA method is based on the reaction of MDA with thiobarbituric acid (TBA) by heating to produce a complex that can be measured spectrophotometrically. One-tenth milliliter of serum or saliva sample was mixed thoroughly with 0.5 ml 20% trichloroacetic acid, 0.05 ml butylated hydroxytoluene and 1.5 ml TBA. The samples were placed in boiling water for 1 h, then cooled to room temperature. Then we added 2 ml butyl alcohol, centrifuged for 10 min at 1200 x g and the absorbance of the supernatant was measured at 532 nm (Ergun et al. 2011). 8-Hydroxy-desoxyguanosine 8-OHdG was measured in both serum and saliva using an enzyme-linked immunosorbent (ELISA) assay kit. We followed the manufacturer’s instructions (Cayman Chemical Co., Ann Arbor, MI). Antioxidant defense system Serum and salivary uric acid measurements were performed immediately after sample collection using kits from Biosystems (Barcelona, Spain). For serum and salivary TAC and GPx measurements, we used kits from Randox (London, UK). The total antioxidant activity method is based on the ability of antioxidant molecules to quench ABTSº radical, a blue-green chromophore with characteristic absorption at 734 nm compared to Trolox, a water soluble vitamin E analogue (Bompadre et al. 2004).

Results The location of the lesions, their clinical type, symptoms, and the age of the lesions are given in Table 1. We found significant differences between the OLP patients and the control group for salivary 8-OHdG (10.50  2.74 vs. 6.47  0.93 ng/mg albumin, respectively, p  0.05), MDA (0.31  0.025 vs. 0.25  0.04 nmol/mg albumin, respectively, p  0.05), uric acid (1.70  0.60 vs. 3.12  0.85 mg/mg albumin, respectively, p  0.05), TAC (0.8  0.15 vs. 1.24  0.16 mmol/mg albumin, respectively, p  0.05), GPx (28.16  11.95 vs. 29.97  17.78 U/mg albumin, respectively, p  0.05), MMP-8 (12.78  2.09 vs. 9.69  0.71 ng/mg albumin, respectively, p  0.05) and CTX I (0.56  0.29 vs. 0.41  0.12 ng/mg albumin, respectively, p  0.05) (Figs. 1, 2). We found significant differences between the OLP patients and the control group for serum 8-OHdG (7.92  0.55 vs. 6.51  0.75 ng/ml, respectively, p  0.05), MDA (0.34  0.02 vs. 0.29  0.12 nmol/l, respectively, p  0.05), uric acid (4.11  0.70 vs. 5.5  0.7 mg/dl, respectively, p  0.05), TAC (1.03  0.13 vs. 1.76  0.16 mmol/l, respectively, p  0.05) and GPx (40.27  24.19 vs. 46.54  14 U/l, respectively, p  0.05), MMP-8 (14.56  3.84 vs. 10.34  9.1 ng/ml, respectively, p  0.5) and CTX I (0.54  0.12 vs. 0.41  0.2 ng/ml, respectively, p  0.5) (Figs. 3  5). We found strongly negative correlations between TAC and GPx (r  -0.43, p  0.004) (Fig. 5) and between uric acid and 8-OHdG (r  -0.6, p  0.005) (Fig. 7) in OLP patient saliva samples.

Table 1.  Clinical data for patients with OLP

Collagen degradation biomarkers MMP-8 and CTX I were measured in both serum and saliva using the ELISA method. We followed the manufacturer’s instructions (R & D Systems, Minneapolis, MN) for MMP-8 and TSZ Scientific LLC (Lexington, KY) for CTX I. Statistics Data are expressed as means  SD, ranges or percentages as appropriate. Pearson’s correlation coefficient was used to test the co-variation of saliva and blood characteristics. The data were analyzed statistically using StataIC 11 (StataCorp. 2009. Stata: Release 11 Statistical Software College Station, TX). A p value  0.05 was considered statistically significant.

Clinical features Localization oral mucosa gingiva lip tongue Clinical type keratosis atrophic/erosive Symptoms no yes Age of lesion  6 months 6  12 months  12 months

Patient number 20 5 3 2 10 20 5 25 2 7 21

n  30.

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Fig. 1.  Mean values for salivary 8-OHdG, uric acid, GPx and MMP-8. *­ Statistically significant.

Discussion Saliva is a complex biological fluid with great potential for diagnostic purposes (Kaufman and Lamster 2002). OS and alterations in the immune system are closely related in many disease processes including oral diseases (Agha-Hosseini et  al. 2012); both appear to contribute to OLP pathogenesis. The literature contains several reports concerning the effects of oxidative stress on OLP (Agha-Hosseini et al. 2012, Scrobotă et al. 2011). Therefore, we studied salivary and serum 8-OHdG, MDA, uric acid, TAC and GPx levels in OLP patients.

Fig. 2.  Mean values for salivary MDA, TAC and CTX I. *­ Statistically significant.

Fig. 3.  Mean values for serum 8-OHdG, uric acid and TAC. ­*Statistically significant.

ROS are produced during inflammation from phagocytes and most have short half-lives. ROS act in phagosomes as agents toxic to microorganisms, fungi, parasites and neoplasmic cells, and thus are an important factor in the intracellular killing mechanism of phagocytes (Agha-Hosseini et al. 2012). ROS can cause substantial damage to tissue and cellular components, e.g., cellular phospholipids, nucleic acids, proteins, carbohydrates and enzymes. We found a significant increase in salivary and serum MDA and 8-OHdG levels in the OLP group compared to controls (Figs. 1, 2). Furthermore, we found significantly decreased TAC, GPx and uric acid levels in the saliva and serum of OLP patients compared to the control group (Figs. 1  4). 8-OHdG currently is used as a biomarker of oxidant-induced

Fig. 4.  Mean values for serum GPx and MMP-8. *­ Statistically significant.

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Fig. 7.  Negative correlation of salivary uric acid and 8-OHdG in saliva of OLP patients.

Fig. 5.  Mean values for serum MDA and CTX I. ­*Statistically significant.

DNA damage and as a risk factor for various cancers including head and neck cancer (Paz-Elizur et al. 2008). Efficient DNA repair mechanisms play important roles in protecting against cancer. Few reports appear in the literature in which 8-OHdG concentration was measured in OLP patient saliva (Agha-Hosseini et  al. 2012). An adaptive increase in antioxidant concentration is observed during the first stage of the oxidative burst in serum or saliva. The subsequent intensification of ROS generation exhausts the antioxidant protective system and decreases TAC in vivo (Mealey 2006). We also have observed this in our study, in the context of OLP. TAC levels alone provide information about the capability of antioxidant mechanisms depending on the disease phase. TAC results cannot be applied to assess past lesions or future ones (Prior and Cao 1999). Therefore, we also measured uric acid and GPx levels in both saliva and serum to achieve better characterization of the antioxidant status. Uric acid is the most important antioxidant in saliva, where thiols concentrations are very low

Fig. 6.  Negative correlation of salivary TAC and GPx in saliva of OLP patients.



(Battino et al. 2008). There are few reports in the literature concerning salivary uric acid concentration in OLP patients (Battino et  al. 2008). In the extracellular environment, including saliva, urate can scavenge hydroxyl radicals, singlet oxygens and peroxynitrites, especially when combined with ascorbic acid or thiols (Sautin et al. 2009). In the OLP patient group, we found significant negative correlations between salivary uric acid levels and salivary 8-OHdG level and between salivary TAC levels with GPx (Figs. 6, 7). The significant decrease in the salivary antioxidant biomarkers, uric acid, GPx and TAC, together with the significant increase in the OS biomarkers, MDA and 8-OhdG, observed in the OLP patient group could be due to increased oral OS with local chronic inflammatory reactions. (Yamamoto et al. 1994). A clear malignant transformation mechanism has not been identified for OLP. The current hypothesis is that chronic stimulation by inflammatory cells causes a local OS that leads to DNA damage to epithelial cells. We showed that local OS caused DNA damage as illustrated by increased levels of salivary 8-OHdG and by the negative correlation between salivary uric acid and 8-OHdG (Fig. 7). The DNA damage in epithelial cells could lead to neoplastic changes (Kawanishi et al. 2006). The significant decrease in important salivary antioxidants, such as uric acid and GPx, and the significant increase of salivary OS biomarkers, MDA and 8-OhdG, observed in OLP could provide a starting point for using these characteristics as oral biomarkers for monitoring or avoiding malignant transformation. There are few reports concerning collagen degradation markers, e.g., CTX I and MMP8 (also known as collagenase-2), for OLP. MMP-8 expression has been associated with improved prognosis in tongue cancer (Pradhan-Palikhe et  al. 2010). The rate of type I collagen degradation has been Biomarkers for oral lichen planus  5

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associated with patient survival and has been proposed as a prognostic marker for oral cancer (Nurmenniemi et  al. 2012). Therefore, we investigated these two collagen degradation markers in our OLP patient group. We found higher levels of salivary CTX I and MMP-8 in the OLP patients compared to the control group (Figs. 1, 2). MMP-8 is released during the maturation of polymorphonuclear leukocytes (PMNs) (Chubinskaya et al. 1996). MMP-8 is glycosylated and stored in subcellular-specific granules, where it subsequently is released in large quantities as PMNs are recruited to a site of inflammation (Chubinskaya et  al. 1996). These investigators demonstrated the ability of non-neutrophil-lineage mesenchymal cells, such as human gingival and periodontal ligament fibroblasts and chondrocytes, to produce MMP-8. Under healthy conditions, tissues are protected from MMP action by tissue inhibitors of metalloproteinases (TIMPs). Under conditions of chronic inflammation, such as OLP, the TIMP levels are low; therefore, they are unable to counteract elevated MMPs, activated neutrophil pro-collagenase (pro-MMP-8) and progelatinase (pro-MMP-9) (Deo and Bhongade 2010). Mobilization and activation of inflammatory cells (lymphocytes and neutrophils) causes secretion of inflammatory proteases (Deo and Bhongade 2010) and increased reaction products such as CTX I. Sutinen et al. (1998) investigated the expression of MMPs and their inhibitors, TIMPs, in clinical samples of OSCC, OLP, dysplasia, lymph nodes, tumor metastases and normal oral mucosa. Although their findings showed significantly greater expression in OSCC, they reported weak MMP 1 and 2 expressions in some cases of OLP. Subsequently, Zhou et  al. (2001) reported increased expression of MMP 1–3 in epithelial OLP cells and MMP-9 in OLP inflammatory infiltrating cells, but not TIMPs. These investigators suggested a role for MMPs in basement membrane disruption, which may enable intraepithelial inflammatory cell migration. Transforming growth factor beta (TGF-b) and bone morphogenic protein-4 (BPM-4) have been suggested to be promoting signals for up-regulation of MMPs (Chubinskaya et al.1996). Chen et al. (2008) studied MMPs, TIMPs and TGF-b in OSCC that developed from previous OLP and found constant expression at levels comparable to those detected in atrophic OLP, which is the form of OLP reported to possess greater malignant potential. These investigators concluded that MMPs play a role in malignant transformation in OLP. We found no significant differences in serum MMP-8 and CTX I, between the OLP patients group

and controls. Our findings suggest that salivary assay may be more sensitive for detecting increased disease-related collagen degradation markers than a serum assay. We believe that MMP-8 and CTX I may be possible markers of inflammation intensity in OLP. Currently, there are no defined criteria that allow one to evaluate which OLP patients are at greater risk of malignant transformation. The possible serum and salivary biomarkers that we evaluated may be important for monitoring OLP patients in the future. More research is required to clarify the precancerous nature of OLP and to identify the subclasses of OLP patients at increased risk for malignant transformation.­­

Acknowledgments Our investigation was supported by the Sectorial Operational Programme Human Programme Human Resources Development (SOP HRD), financed by the European Social Fund and by the Romanian Government under contract number POSDRU/6/1.5/S/S17. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this paper.

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Possible salivary and serum biomarkers for oral lichen planus.

There are few reports concerning the potential for clinical application of oxidative stress (OS) and collagen degradation markers in oral lichen planu...
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