|Year : 2017 | Volume
| Issue : 2 | Page : 85-90
Estimation of CCL2/MCP-1 levels in serum and gingival crevicular fluid in periodontal health, disease and after treatment – A clinico biochemical study
Dandu S M Babu1, Sathrawada Poornodaya2, Kotu A Sai3, Deepa Anumala4, Dandu S S P Reddy4, Nagireddy R Reddy4
1 Department of Dentistry, Sri Padmavathi Medical College for Women, SVIMS, Tirupati, Andhra Pradesh, India
2 Department of Periodontics, KMC Hospital, Sadhana Multispeciality Hospital, Divyapur, Auraiyadh, Uttar Pradesh, India
3 Pondicherry Institute of Medical Sciences, Pondicherry, India
4 Department of Periodontics, CKS Teja Institute of Dental Sciences, Tirupati, Andhra Pradesh, India
|Date of Web Publication||8-Jan-2018|
Dandu S M Babu
Department of Dentistry, Sri Padmavathi Medical College for Women, SVIMS, Tirupati, Andhra Pradesh
Source of Support: None, Conflict of Interest: None
Background: The objective of the present study was to evaluate the role of monocyte chemoattractant protein-1 (MCP-1), in periodontal disease (PD) progression and also to investigate the effect of periodontal therapy on MCP-1 concentration in serum and gingival crevicular fluid (GCF). Materials and Methods: Clinical parameters including gingival index, pocket probing depth, and clinical attachment level were recorded for 60 subjects, who divided into four groups. Group I (healthy, n = 20), Group II (gingivitis, n = 20), Group III (chronic periodontitis, n = 20), and Group IV (after treatment group, n = 20). Scaling and root planning (SRP) was performed, and GCF and serum were collected initially and after 12 weeks of treatment. MCP-1 levels were estimated using enzyme-linked immunosorbent assay. Results: The mean MCP-1 concentration in GCF and serum was found to be the highest in Group III, and significantly defers from Groups I, II, and IV. The results of present study also suggest that MCP-1 levels increased progressively in GCF and serum from healthy to periodontitis subjects and levels decreased considerably after SRP. Conclusion: As the PD progresses, there is a substantial increase of MCP-1 concentrations in serum and GCF. The data indicate that high GCF and serum levels of MCP-1 are at a significantly greater risk for the progression of periodontitis. However, controlled, longitudinal studies are needed to confirm this possibility.
Keywords: Gingival crevicular fluid, monocyte chemoattractant protein-1, scaling and root planning, serum
|How to cite this article:|
Babu DS, Poornodaya S, Sai KA, Anumala D, Reddy DS, Reddy NR. Estimation of CCL2/MCP-1 levels in serum and gingival crevicular fluid in periodontal health, disease and after treatment – A clinico biochemical study. J Orofac Sci 2017;9:85-90
|How to cite this URL:|
Babu DS, Poornodaya S, Sai KA, Anumala D, Reddy DS, Reddy NR. Estimation of CCL2/MCP-1 levels in serum and gingival crevicular fluid in periodontal health, disease and after treatment – A clinico biochemical study. J Orofac Sci [serial online] 2017 [cited 2019 Jun 18];9:85-90. Available from: http://www.jofs.in/text.asp?2017/9/2/85/222383
| Introduction|| |
Periodontal disease (PD), a chronic inflammatory disease of the attachment structures of the teeth, is one of the most prevalent forms of bone pathology in humans, besides being a modifying factor of the individual’s systemic health. The bacterial biofilm attached to the surface of the tooth, close to the periodontium, is the etiologic factor for this disease. The inflammatory and immune responses, initiated by periodontopathogens, are thought to protect the host against infection. However, the persistence of a local chronic host response may alter the protective roles of inflammatory cells and produce deleterious effects in these tissues. In fact, the development of the PDs seems to be related to the progression of the inflammatory cell infiltrate into the deeper periodontal tissues.
The presence of chemokines is considered to be one of the inflammatory factors which appear to play a crucial role in mediating the extravasation and accumulation of selective leukocyte subsets in the process of inflammation. The chemokines are chemotactic cytokines that induce the recruitment of well-defined leukocyte subsets unlike the classic leukocyte chemoattractants do, thus, account for the formation of specific inflammatory infiltrate. A common feature of these molecules is the presence of four conserved cysteine residues. Two main subfamilies, CXC (or a) and CC (or b) chemokines are distinguished according to the position of the first two cysteines, which are separated by one aminoacid (CXC) or adjacent (CC). Chemokines activate their functions through interaction with a family of guanosine triphosphate-binding protein-coupled seven-transmembrane domain receptors. Monocyte chemoattractant protein-1 (MCP-1), also known as small inducible cytokine A2 (SCYA2) or CCL2 (CC chemokine 2 ligand), is a well-characterized member of CC chemokine family and was originally described as a potent chemoattractant for monocytes. MCP-1 exerts its action mostly through the interaction with its receptor CCR2.
MCP-1 was found to be preferentially expressed in diseased periodontal sites, and presented a differential spatial distribution in the periodontal tissues, because it is expressed along the basal layer of the oral epithelium and by endothelial cells, fibroblasts, and mononuclear phagocytes in the inflammatory infiltrate. MCP-1 is supposed to be the major chemo attractant of macrophages in PDs. Thus, the chemo attraction of macrophages by MCP-1 could contribute to enhanced severity of PDs, a hypothesis supported by an analysis of data showing that greater number of macrophages were found in active sites of periodontitis, and that MCP-1 activity in gingival crevicular fluid (GCF) increased with severity of the disease.
GCF is a complex mixture of substances derived from serum, leukocytes, and structural cells of the periodontium and oral bacteria. These substances possess a great potential for serving as indicators of PD and healing after therapy.
The composition of the GCF is the result of the interplay between the bacterial biofilm adherent to the tooth surfaces and the cells of the periodontal tissues. The collection of GCF is a minimally invasive procedure, and the analysis of specific constituents in the GCF provides a quantitative biochemical indicator for the evaluation of the local cellular metabolism that reflects a person’s periodontal health status.
In the light of above facts, the present study is designed to evaluate the role of MCP-1 in PD progression and also to investigate the effect of periodontal therapy on MCP-1 concentration in serum and GCF.
| Materials and Methods|| |
The study population consisted of 60 subjects (18 women and 42 men), 23–53 years of age, who were selected from an outpatient section of our department. The study was discussed with the subjects, and written, informed, signed consent was obtained from participants who agreed to participate voluntarily. The study protocol was approved by the institution’s ethical committee (No. cks/ethics/0042/2013) on 18/01/2013. Inclusion criteria included individuals, who had not received periodontal therapy within the preceding 6 months and who had at least ≥20 natural teeth. The patients with some systemic diseases that could impact the progression of PD or which can alter the course of PD, such as diabetes, hypertension, heart diseases, rheumatoid arthritis, respiratory diseases, anti-inflammatory, and antibiotics, or who had received periodontal therapy in the preceding 6 months, as well as pregnant and lactating females, were excluded from the study.
Subjects with chronic periodontitis and gingivitis as well as healthy control subjects were diagnosed based on the periodontal classification of American Academy of Periodontology and met with the following criteria:
- Group I (healthy) consisted of 20 subjects with clinically healthy periodontium, gingival index (GI) = 0, pocket probing depth (PPD) ≤ 3 mm, clinical attachment level (CAL) = 0, and with no evidence of bone loss on radiographs.
- Group II (gingivitis) consisted of 20 subjects, who showed clinical signs of gingival inflammation, with GI > 1, PPD ≤ 3 mm, and CAL = 0 and no radiographic bone loss.
- Group III (chronic periodontitis) consisted of 20 subjects who had signs of clinical inflammation again with GI > 1, along with a PPD ≥ 5 mm and CAL ≥ 3 mm with the radiographic evidence of bone loss at more than 10 sites.
- Group IV (post-treatment group): Patients in Group III were treated with a scaling and root planning (SRP) formed Group IV (post-treatment group), in whom GCF samples were collected from the same site 12 weeks after treatment.
All subjects underwent a clinical examination including the following periodontal clinical parameters: GI, PPD, and CAL. One examiner (PR) performed all the measurements at six sites for all teeth by using a UNC-15 periodontal probe to ensure adequate intra-examiner reproducibility. Assessment of GI, PPD, CAL, and MIP-1α levels in GCF and serum was performed at baseline and 12 weeks after therapy.
Collection of gingival crevicular fluid
One examiner performed all the clinical and radiological examinations, group allocations and selection of sampling site, and samples were collected on subsequent day by second examiner. All these were endeavored to ensure masking of the sampling examiner and to avoid contamination of GCF with blood-associated probing of inflamed sites. On next day of clinical examination, the identified site was isolated with cotton roll and saliva ejector to avoid salivary contamination. The site was gently air-dried, and clinically detectable supragingival plaque was removed using curette without touching the marginal gingiva. GCF was collected by placing the microcapillary pipette at the entrance of the gingival sulcus. From each site, a standardized volume of 1 μl GCF was collected using calibration on white color-coded 1–5 μl calibrated volumetric microcapillary pipette (Sigma–Aldrich, USA). Periodontal treatment, that is, SRP was performed for CP patients (at same appointment) after GCF collection. After 12 weeks, GCF was collected from same site. The collected GCF samples were placed immediately into individual microcentrifuge tubes containing 300 μl of phosphate-buffered saline. The samples were stored at −70°C till the time of assay. During the 12 weeks period, subjects were seen at 1-week intervals, and plaque control measures were performed.
Collection of serum
Five milliliters of blood was collected from the antecubital fossa by venipuncture using a 20-gauge needle with 5-ml of syringe. The serum was separated from blood by centrifuging at 3000×g for 10 min and immediately transferred to a plastic vial and stored at −70°C until the time of assay.
Determination of monocyte chemoattractant protein-1α in gingival crevicular fluid and serum samples
MCP-1 levels in GCF and serum were determined using a solid phase sandwich enzyme-linked immunosorbent assay (ELISA, Cat. No. RHF430CKC, Antigenix America Inc., USA) according to the manufacturer’s instructions. The samples were run in triplicate to ensure accuracy and to provide enough data for statistical validation of the results. An ELISA reader (Biorad, USA) with a 450 nm as primary wavelength and 655 nm as the reference wavelength was used to measure the absorbance of the substrate. The concentration of MCP-1 in the tested sample was evaluated using the standard curve plotted using the absorbance value obtained for the standards provided with the kit.
All the data were analyzed using a software program (Statistical Package for the Social Sciences version 11.5, SPSS Inc., Chicago, IL, USA). Sample size of 20 has been taken, which was found to be adequate to achieve more than 80% power at 0.1 level of significance. Group comparisons for non-parametric variables were performed by using the Kruskal–Wallis test. In addition, pairwise comparisons using the Mann–Whitney U test were made to explore which pair or pairs differed. The statistical significance of MCP-1α concentrations before and after treatment was analyzed using Wilcoxon test. Spearman correlation analysis was used to identify any association between GCF MCP-1α concentrations and clinical parameters.
| Results|| |
The mean MCP-1 concentration in GCF and serum was found to be the highest in Group III; the mean MCP-1 concentration in Group II was found to lie in between the concentrations obtained in Groups I and III as shown in [Table 1].
|Table 1: Descriptive statistics of baseline parameters in the study population (mean ± standard deviation)|
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To test the hypothesis of equality of means among the four groups, non-parametric Kruskal–Wallis test was conducted, which indicated that the means differ significantly among the groups (P ≤ 0.05) [Table 2]. The results suggest that MCP-1 levels increased progressively in GCF and serum from healthy to periodontitis. Further multiple comparisons using Mann–Whitney U test were conducted to find out which pair or pairs differ significantly in GCF and serum. The results showed that the differences were statistically significant between Groups I and II, Groups I and III, Groups II and III, Groups II and IV and Groups III and IV [P < 0.005; [Table 3].
|Table 2: Results of Kruskal–Wallis test comparing mean MCP-1 concentration in serum and GCF between four groups|
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|Table 3: Pair wise comparison using Mann–Whitney U test for GCF and serum MCP-1|
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When Group IV and Group III of GCF and serum were compared using Wilcoxon signed rank test, the difference in the concentrations of MCP-1 was statistically significant suggesting that after SRP, MCP-1 levels decreased considerably [Table 4]. Spearman’s rank correlation test was conducted to find correlation between clinical parameters, that is, GI, PPD, CAL, and MCP-1 concentration in GCF and serum. It showed a significant positive correlation between MCP-1 concentration and clinical parameters in Groups III and IV [Table 5].
|Table 4: Results of Wilcoxon signed rank test to compare MCP-1 in GCF and serum of Groups III and IV|
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|Table 5: Results of Spearman correlation test between GCF and serum MCP-1 and clinical parameters|
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Confidence interval was calculated for differentiating the limits of GCF and serum MCP-1 values in different groups to consider MCP-1 as an inflammatory biomarker. Differentiating values with probability 0.95 for different groups were as shown in [Table 6] and [Table 7].
| Discussion|| |
The inflammatory oral diseases are characterized by the persistent migration of polymorpho nuclear leukocytes, monocytes, lymphocytes, plasma cells, mast cells, and osteoblasts and osteoclasts. Chemokines like MCP-1 are responsible for the selective recruitment and activation of these cells at inflammatory sites.
Many studies had been undertaken to estimate the levels of MCP-1 in GCF and serum. Hanazawa et al. have shown that cell components of Porphyromonas gingivalis induce MCP-1 gene expression in the gingival tissues of periodontal patients. Yu and Graves reported that in moderately and highly inflamed areas, the extent of MCP-1 expression is greater than that in adjacent normal/mildly inflammed areas, and principal cell type expressing MCP-1 in dense inflammatory infiltrates is mononuclear phagocyte. Gupta et al. stated that the levels of MCP-1 is significantly higher in GCF, serum, and saliva in chronic periodontitis patients when compared to healthy controls and decreased in patients after periodontal therapy. Kurtis et al. shown that in chronic and aggressive periodontitis patients, both total amount and concentration of MCP-1 were higher in GCF as compared to healthy patients.
Earlier studies used filter paper strips and periotron 8000 and 6000, which can result in non-specific attachment of the analyte to filter paper fibers ensuing in a false reduction in the detectable MCP-1 levels, which underestimates the correlation of levels of MCP-1 to disease. In the present study, the extracrevicular (unstimulated) method of GCF collection using microcapillary pipettes is performed to ensure atraumatism, to obtain an undiluted sample of native GCF, the volume of which could be accurately assessed, and to avoid non-specific attachment of the analyte to filter-paper strips.
When present study is compared to that of Thunell et al. and Emingil et al., where chronic periodontitis, after treatment groups was not included, having additional group of chronic periodontitis and after treatment, assisted us better to evaluate the role played by MCP-1 in the different stages of PD and the effect of periodontal therapy on MCP-1 concentrations.
In the present study, the mean concentrations of MCP-1 in GCF were found to increase proportionally from healthy to periodontitis, while in gingivitis the mean concentrations of MCP-1 fell between two groups. The results of the present study are in accordance with Thunell et al., Pradeep et al., and Garlet et al. The result of the present study contrary to the results of Offenbacher et al. reported that there is suppression of MCP-1 in experimental gingivitis patients when compared to healthy controls. In the present study levels of MCP-1 in GCF decreased from chronic periodontitis patients toward after treatment group in accordance with Fokkema et al. When CP patients were treated SRP with strict oral hygiene measures, the mean concentration of MCP-1 in GCF reduced after treatment. This decrease in MCP-1 concentration further correlated positively with the decrease in scores of clinical parameters, suggesting its association with the severity of disease. This strongly suggests that any interventional therapy designed to improve the periodontal status would not only affect the levels of inflammatory markers in the oral micro-environment but also may have equally significant suppressive effects on the systemic plane.
The variability of MCP-1 concentrations within patients of each group could be attributed to the role of MCP-1 in different stages of disease process at the time of collection of GCF and serum samples. The high concentration of serum MCP-1 in three participants (0.147, 0.145, and 0.143 ng/μl) in the healthy group could has been due to the subclinical inflammation or allergy or any infection not reported by patients. Low MCP-1 levels were found in two GCF samples of patients with periodontitis (0.081 ng/μl and 0.081 ng/ml) which may be because this diseased site was probably stable. The wide range observed in levels of MCP-1 in gingivitis and periodontitis could result, in part, from differences in disease activity and crevicular fluid flow at the time of collection, as well as from variations in the number of defense cells migrating into the crevice, differences in expression of MCP-1 receptors and interaction between MCP-1 and MCP-1 receptor.
The differentiating values with probability 0.95 have shown that GCF MCP-1 concentration ≤0.031 ng/μl suggests periodontal health, from 0.031 to 0.077 ng/μl gingivitis and concentration ≥0.077 ng/μl suggests chronic periodontitis and serum MCP-1 concentration ≤0.147 ng/μl suggests periodontal health, from 0.321 to 0.354 ng/μl gingivitis and concentration ≥0.509 ng/μl suggests chronic periodontitis. Thus, its role as an inflammatory biomarker in PD can be proposed.
Periodontal infections are not only localized to the marginal periodontium but also patients present increased systemic inflammation that was indicated by elevated serum levels of various inflammatory markers when compared to those in unaffected control populations. The GCF is a serum transudate that is enriched with microbial and host products that arise as a result of the current inflammatory dynamics of the host–biofilm interaction. In the present study, both GCF and serum were evaluated for the change in the levels of MCP-1 between health and diseased individuals.
In the present study, the mean concentrations of MCP-1 in serum were found to increase proportionately from healthy to periodontitis, while in gingivitis, the mean concentrations of MCP-1 fell between two groups. The results of the present study are in accordance with de Queiroz et al., Anil et al., and Pradeep et al. The possible reason for increase in serum MCP-1 could be either spill over from the GCF or gingival tissues to peripheral circulation or it could be due to systemic inflammatory response to progressive disease in the periodontal pocket.When the CP patients were treated by SRP with strict oral hygiene measures, the mean concentration of MCP-1 in serum reduced after treatment. This decrease in MCP-1 concentration further correlated positively with the decrease in scores of clinical parameters, suggesting its association with the severity of disease.
The presence of high serum levels of MCP-1 has also been detected in other diseases such as cerebrospinal fluid of acquired immune deficiency syndrome patients with cytomegalo virus encephalitis, diabetic retinopathy, neuropathy, nephropathy, ischemic stroke, and myocardial infarction. These studies have suggested that MCP-1 may play an important role in producing the pathogenic state of systemic inflammatory disease. Although not proven, but such a possibility of increased risk of other diseases due to increased MCP-1 levels in serum can pave the way to future studies to correlate MCP-1 levels in serum and GCF and to explore the actual potential risk associated with it. If subsequent research confirms that PD is a true risk factor for systemic diseases and the initiation or progression of these medical conditions can be reduced by periodontal treatment, then further integration of dental and general medicine can open new opportunities for diagnosis and treatment. By greater integration of medicine and dentistry, dentists can take more responsibility for the management of their patients’ systemic health, and conversely the physicians can assume a more active role in their patients’ oral health.
The results of the present study indicate that the concentration of MCP-1 in GCF and serum increased proportionately with the severity of disease. The proportionate increase in levels from healthy to gingivitis to periodontitis groups further confirmed that MCP-1 was actively secreted by the predominant cells of PD activity.
| Conclusion|| |
In the light of the present study results, it can be concluded that the mean concentrations of MCP-1 in diseased group were significantly higher than that in healthy and after treatment groups. These data indicate that the high GCF and serum levels of MCP-1 are at significantly greater risk for the progression of periodontitis. Thus, this study is useful in assessing the health, disease status of periodontal tissues, and efficacy of clinical treatment accompanied by reduction in MCP-1.
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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], [Table 7]