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Tumor Necrosis Factor- -converting Enzyme (TACE) Levels in Periodontal Diseases
N. Bostanci1,
G. Emingil2,
B. Afacan2,
B. Han2,
T. Ilgenli2,
G. Atilla2,
F.J. Hughes1 and
G.N. Belibasakis1,*
1 Centre for Adult Oral Health, Bart’s and the London School of Medicine and Dentistry, Queen Mary University of London, Turner Street, E1 2AD London, UK; and
2 Department of Periodontology, School of Dentistry, Ege University,  zmir, Turkey
Correspondence: * corresponding author, g.belibasakis{at}qmul.ac.uk
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ABSTRACT
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Tumor necrosis factor- -converting enzyme (TACE) is a metalloprotease which can shed several cytokines from the cell membrane, including receptor activator of NF- B ligand (RANKL). This study aimed to investigate the hypothesis that TACE would be elevated in the gingival crevicular fluid (GCF) of persons with periodontitis. Total TACE amounts in GCF were higher in persons with chronic and aggressive periodontitis than in those with gingivitis or in healthy persons. TACE concentrations in GCF were higher in persons with chronic and aggressive periodontitis than in those with gingivitis, although not significantly higher than in healthy persons. Persons with chronic periodontitis receiving immunosuppressive treatment exhibited over 10-fold lower TACE levels than the other periodontitis groups. TACE was positively correlated with probing pocket depth, clinical attachment levels, and RANKL concentrations in GCF. In conclusion, the increased GCF TACE levels in persons with periodontitis and their positive correlation with RANKL may indicate an association of this enzyme with alveolar bone loss, and may warrant special attention in future therapeutic approaches.
Key Words: TACE • gingival crevicular fluid • RANKL • bone resorption • periodontal diseases
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INTRODUCTION
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Tumor necrosis factor--converting enzyme (TACE) is a type I transmembrane protein with an extracellular zinc-dependent protease domain with the capacity to cleave or shed the ectodomain of several membrane-bound proteins (Black et al., 1997; Moss et al., 1997; Reddy et al., 2000). It is also known as a member of the "A Disintegrin And Metalloprotease" (ADAM) family, namely, ADAM17. TACE is reportedly produced by several cell types, including T-lymphocytes and monocytes (Black et al., 1997; Lum et al., 1999). By shedding cytokines from the cell surface, TACE regulates their release into the local microenvironment, contributing to the establishment of inflammation. The protein substrates that TACE is able to shed are ligands and receptors highly associated with inflammation, such as tumor necrosis factor- and its p55 receptor, transforming growth factor- , and interleukin-1 receptor II (Reddy et al., 2000; Black, 2002), and Receptor Activator of NF-B Ligand (RANKL) (Lum et al., 1999; Nakashima et al., 2000). RANKL, a member of the tumor necrosis factor ligand family, is required for triggering osteoclastogenesis and activating bone resorption (Teitelbaum, 2000). It can be found in both membrane-bound and soluble forms, and these may exhibit functional differences (Nakashima et al., 2000; Mizuno et al., 2002; Nakamichi et al., 2007). Models of periodontal disease in vivo have demonstrated the crucial role of RANKL in the regulation of bone destruction, and have highlighted the importance of activated T- and B-cells in this process (Teng et al., 2000; Taubman et al., 2005; Han et al., 2006). It is now evident that RANKL holds a key role in the emerging concepts of periodontal disease pathogenesis (Taubman et al., 2007).
Clinical studies of human periodontal disease clearly indicate that RANKL expression levels are elevated in the diseased tissues (Crotti et al., 2003; Liu et al., 2003; Garlet et al., 2004; Kawai et al., 2006; Lu et al., 2006; Bostanci et al., 2007b) and in gingival crevicular fluid (GCF) (Mogi et al., 2004; Vernal et al., 2004; Lu et al., 2006; Nishijima et al., 2006; Bostanci et al., 2007a). The detection of RANKL protein in GCF by enzyme-linked immunosorbent assay (ELISA) indicates that its presence in this biological exudate is in soluble form. This would imply that it is somehow shed from the cell membrane, possibly through the action of host proteolytic enzymes present in GCF (Uitto et al., 2003). The observations that RANKL levels are elevated in GCF of persons with periodontitis, and that TACE can shed RANKL from the cell membrane more efficiently than other enzymes (Lum et al., 1999), suggest the possibility that TACE levels in GCF would also be elevated in periodontitis. Thus, this study aimed to investigate the hypothesis that GCF TACE levels are elevated in persons with destructive periodontitis. The specific objective was to compare the GCF levels of TACE between groups of healthy individuals and those with gingivitis, chronic periodontitis, generalized aggressive periodontitis, and chronic periodontitis exhibiting gingival overgrowth under immunosuppressive treatment.
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MATERIALS & METHODS
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Study Population and Clinical Examination
In total, 107 individuals were included in this study, recruited from the Department of Periodontology, School of Dentistry, Ege University, zmir. The same cohort of persons was used in our recently published work to investigate the concentrations of RANKL (Bostanci et al., 2007a). The use of human subjects satisfied the requirements of Ege University Institutional Review Board and was conducted in accordance with the Helsinki Declaration. Written and informed consent was obtained from each person prior to enrollment in the study. The selection of the participants was made according to the clinical and radiographic criteria proposed by the 1999 International World Workshop for a Classification of Periodontal Disease and Conditions (Armitage, 1999). Clinical periodontal examination included measurement of probing pocket depth, clinical attachment level at 6 sites around each tooth with a manual probe, full-mouth papilla bleeding index, and plaque index. The healthy group consisted of 11 females and 10 males (from 16 to 59 yrs old; mean age, 29.6 ± 15.0 yrs) with no clinical signs of gingival inflammation or radiographic evidence of alveolar bone loss, mean probing pocket depth 1.9 ± 0.3 mm, and mean GCF volume 0.11 ± 0.05 µL. The gingivitis group included nine females and 13 males (from 14 to 63 yrs old; mean age, 31 ± 15 yrs), who exhibited various degrees of gingival inflammation, no radiographic evidence of alveolar bone loss, mean probing pocket depth 2.86 ± 0.34 mm, plaque index 1.82 ± 0.72, papilla bleeding index 2.36 ± 0.83, and mean GCF volume 0.30 ± 0.15 µL. The generalized aggressive periodontitis group consisted of 16 females and nine males (from 18 to 38 yrs old; mean age, 29.4 ± 4.9 yrs), with mean probing pocket depth 7.64 ± 1.72 mm, clinical attachment loss 8.4 ± 2.16 mm, plaque index 1.2 ± 0.5, papilla bleeding index 2.2 ± 1.5, and mean GCF volume 0.43 ± 0.24 µL. The group with chronic periodontitis included 13 females and 15 males (from 39 to 64 yrs old; mean age, 51.0 ± 6.6 yrs), with mean probing pocket depth 6.33 ± 1.30 mm, clinical attachment loss 7.8 ± 1.27 mm, plaque index 1.0 ± 0.38, papilla bleeding index 2.0 ± 1.42, and mean GCF volume 0.38 ± 0.17 µL. The group with chronic periodontitis and under immunosuppressive treatment included eight females and three males (from 16 to 54 yrs old; mean age, 34.4 ± 11.6 yrs), who were renal transplant patients receiving cyclosporin-A, azathioprine, and prednisolone (Bostanci et al., 2007a). They exhibited gingival overgrowth (hyperplasia index 3), mean probing pocket depth 5.77 ± 0.8 mm, clinical attachment loss 6.2 ± 1.3 mm, plaque index 2.0 ± 0.97, papilla bleeding index 2.45 ± 1.59, and mean GCF volume 0.74 ± 0.24 µL.
Collection of GCF
Gingival crevicular fluid samples were collected from the mesiobuccal aspects of single-rooted teeth. The selected sites were cleared of supragingival plaque, isolated with cotton rolls, and dried with a gentle stream of air, and then a sterile Periopaper strip (ProFlow Inc., Amityville, NY, USA) was gently inserted into the periodontal pocket for 30 sec. The GCF sample volume was measured with a calibrated Periotron 8000 (ProFlow), and the readings were converted to an actual volume (µL) by reference to a standard curve. Samples were lyophilized, re-eluted in 200 µL of phosphate-buffered saline (PBS, pH 7.2), shaken gently for 1 min, then centrifuged at 2000 g for 15 min at 4° C, and finally frozen at –80° C until being processed for the TACE ELISA assay.
Analysis of TACE Levels in GCF
The amount of TACE in the GCF samples was determined by means of a commercially available human-specific ELISA kit, in accordance with the manufacturer’s instructions (DuoSet ELISA Development kit, R&D Systems, Abington, UK). The sensitivity of the assay was 39 pg/mL. The levels of TACE in each GCF sample were expressed in total amounts (pg/30 sec), as well as concentrations calibrated against GCF volume (pg/µL), since the former approach is recommended for the measurement of enzyme levels (Lamster et al., 1994), whereas the latter is recommended for inflammatory mediators (Chung et al., 1997) in GCF.
Statistical Analysis
Statistical analysis was performed by non-parametric methods. Comparisons among all groups were performed by the Kruskal-Wallis test. When significant differences were observed (p < 0.008), then two-group comparisons were assessed with Mann-Whitney U tests, and p < 0.05 was considered to be statistically significant. To analyze the correlations between GCF TACE levels and clinical parameters, we used Spearman’s rank correlation analysis. We used our previously published data on the concentrations of RANKL in the same GCF samples (Bostanci et al., 2007a) to investigate the correlation between RANKL and TACE concentrations in GCF. All data analyses were performed with SPSS 12.0 software.
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RESULTS
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Clinical Findings of Sampling Sites
The groups with chronic and aggressive periodontitis had significantly higher mean probing pocket depths and clinical attachment loss scores of sampling sites than did the healthy group and those with gingivitis (p < 0.05). The mean probing pocket depth and clinical attachment level scores of sampling sites in the groups with chronic periodontitis and immunosuppressed chronic periodontitis were similar. No significant differences were detected between the gingivitis and periodontitis groups regarding the papilla bleeding index and plaque index of sampling sites (p > 0.05).
Analysis of GCF TACE Levels
The distributions of both total amounts and concentrations of TACE in GCF were investigated. TACE was detected in 11/21 healthy persons, 12/22 of those with gingivitis, 24/28 in those with chronic periodontitis, 22/25 in those with aggressive periodontitis, and 4/11 in immunosuppressed persons with chronic periodontitis. The total amounts of TACE in GCF (mean ± standard error) were 9.21 ± 2.4 pg in the healthy group, 17.47 ± 4.65 pg in those with gingivitis, 43.11 ± 6.18 pg in those with chronic periodontitis, 46.6 ± 7.85 pg in those with aggressive periodontitis, and 4.3 ± 2.25 pg in the immunosuppressed group with chronic periodontitis (Fig. 1 ). The concentrations of TACE in GCF (mean ± standard error) in these groups were 88.5 ± 21.89 pg/µL, 60.83 ± 19.35 pg/µL, 142.91 ± 21.2 pg/µL, 121 ± 24.2 pg/µL, and 6.41 ± 3.1 pg/µL, respectively (Fig. 2). When the groups with chronic and aggressive periodontitis were compared, there were no significant differences in either total amounts or concentrations of TACE in GCF. Likewise, no significant differences were observed among the healthy, gingivitis, and immunosuppressed chronic periodontitis groups. However, both the aggressive and chronic periodontitis groups exhibited significantly higher total amounts of TACE compared with the healthy (p < 0.001) or gingivitis (p < 0.005) group. Although the groups with aggressive and chronic periodontitis also exhibited numerically higher TACE GCF concentrations compared with the healthy group, the former difference did not prove to be significant (p = 0.259), whereas the latter was only marginally insignificant (p = 0.055). Nevertheless, in the case of gingivitis, TACE GCF concentrations were significantly lower compared with concentrations in both the chronic and aggressive periodontitis groups (p < 0.05). Importantly, both total amounts and concentrations of TACE in GCF were significantly lower in the immunosuppressed group with chronic periodontitis, compared with either the chronic or aggressive periodontitis group (p < 0.001).
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Figure 1. Distribution of total TACE amounts in GCF from healthy persons (n = 21), those with gingivitis (n = 22), chronic periodontitis (n = 28), aggressive periodontitis (n = 25), and immunosuppressed persons with chronic (IS-Chronic) periodontitis (n = 11). The individual values represent the total amounts of TACE (pg/30 sec) in each person. Values significantly different from those in healthy persons (*p < 0.001) and those with gingivitis (+p < 0.005).
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Figure 2. Distribution of TACE concentrations in GCF from healthy persons (n = 21), those with gingivitis (n = 22), chronic periodontitis (n = 28), aggressive periodontitis (n = 25). and immunosuppressed persons with chronic (IS-Chronic) periodontitis (n = 11). The individual values represent the concentrations of TACE (pg/µL) in each person. Values significantly different from those in persons with gingivitis (*p < 0.001) and immunosuppressed persons with chronic periodontitis (+p < 0.005).
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We then used Spearman’s rank correlation analysis to investigate the correlation between GCF TACE levels and clinical parameters (Table). Both total TACE amounts and TACE concentrations were positively correlated with probing pocket depth and clinical attachment levels, but not with papilla bleeding index or plaque index.
We used the same statistical analysis to investigate the correlation between the TACE concentrations detected in the present study and the previously reported RANKL concentrations (Bostanci et al., 2007a) in the same GCF samples (Fig. 3). Interestingly, the results indicated a positive correlation between TACE and RANKL concentrations in GCF (r = 0.243, p = 0.006).
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Figure 3. Scatter plot showing the correlation between TACE and RANKL concentrations (pg/µL) in GCF. A positive correlation was revealed (r = 0.243, p = 0.006). These GCF RANKL concentration data have previously been reported (Bostanci et al., 2007a).
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DISCUSSION
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The present study is the first to investigate the involvement of TACE in periodontal diseases, demonstrating that total TACE amounts in GCF are elevated in chronic and aggressive periodontitis, compared with health or gingivitis. Accordingly, TACE concentrations in GCF were higher in persons with chronic and aggressive periodontitis than in those with gingivitis, but not significantly different from those in healthy persons. This discrepancy is attributed to the higher GCF volumes in persons with periodontal diseases compared with healthy persons, which may result in decreased inflammatory mediator concentrations in the samples (Chung et al., 1997).
Since TACE is an enzyme responsible for shedding several cell-membrane-bound cytokines (Black, 2002), its elevated levels observed in persons with periodontitis may constitute a biological mechanism that promotes diffusion of soluble inflammatory mediators in the periodontium. Subsequently, these soluble factors could act in a paracrine rather than juxtacrine manner, to induce periodontal tissue destruction, including alveolar bone resorption. The fact that TACE levels in gingivitis are significantly lower than in either chronic or aggressive periodontitis, but not different from levels in healthy persons, suggests a potential association between alveolar bone destruction and the occurrence of this molecule in GCF.
It has been demonstrated that RANKL, a key factor for the induction of osteoclastogenesis and bone resorption, is a substrate with high specificity to the enzymatic activity of TACE (Lum et al., 1999; Schlondorff et al., 2001). Therefore, TACE is an important regulator of RANKL shedding and tissue release, with potential involvement in bone destruction. Interestingly, the pattern of TACE levels observed in the present study resembled those of RANKL levels previously reported in the same GCF samples (Bostanci et al., 2007a). Therefore, we further considered the relationship between these 2 molecules and hypothesized a putative correlation in GCF. Indeed, a positive correlation between TACE and RANKL concentration in GCF was demonstrated, indicating that these 2 factors could be functionally related. This notion is further supported by a previous report demonstrating colocalization of RANKL and TACE around loosened joint prostheses (Horiki et al., 2004).
In the present study, a positive correlation was also demonstrated between TACE levels and probing pocket depth or clinical attachment levels, but not papilla bleeding index or plaque index. Although these findings could suggest a potential association of TACE with bone loss, but not inflammation, the correlations proved to be too weak to support a biological significance. We have previously shown that the presence of RANKL in GCF (Bostanci et al., 2007a) or mRNA expression in gingival tissue (Bostanci et al., 2007b) was correlated with the same clinical parameters.
Activated T-cells release large amounts of RANKL (Kong et al., 1999; Weitzmann et al., 2001; Nakamichi et al., 2007) and are considered a major source of this molecule, as well as a key cell population implicated in the pathogenesis of human periodontitis (Teng, 2006; Taubman et al., 2007). In conjunction with T-cells, recent evidence also highlights a crucial role for B-cells in RANKL-mediated bone destruction in periodontitis (Kawai et al., 2006). Immunosuppressed persons with chronic periodontitis, who have impaired T-cell function, exhibit lower GCF levels of RANKL compared with levels in systemically healthy persons with chronic periodontitis (Bostanci et al., 2007a), denoting that T-cells are largely responsible for releasing soluble RANKL in GCF. Shedding of RANKL from the surfaces of T-cells is mediated by TACE, and a high expression of TACE is concurrent with a high expression of RANKL (Nakamichi et al., 2007). Moreover, immunosuppression has been previously shown to down-regulate TACE activity (Zhang et al., 2000). It was therefore anticipated that TACE levels would be reduced in the GCF of immunosuppressed persons with chronic periodontitis, following the RANKL pattern. Indeed, in the present study, TACE was detected in only 36% of these individuals, and at more than 10-fold-lower levels than either chronic or aggressive periodontitis. This finding may highlight the involvement of T-cells in the production and secretion of TACE, which could in turn regulate the shedding of RANKL and its release into GCF.
In conclusion, the present study has shown that TACE levels in GCF may be associated with periodontitis, reveals a potential correlation with RANKL levels, and implicates cells of the immune system in its production and release. The enzymatic activity of TACE constitutes a target for therapeutic approaches to prevent bone destruction in rheumatoid arthritis and osteoarthritis, especially by the exogenous application of synthetic inhibitors (Black, 2002; Moss and Bartsch, 2004; Burrage and Brinckerhoff, 2007). It may therefore be of interest to consider the inhibition of TACE in the development of future therapeutic approaches for periodontitis. Nevertheless, due to the cross-sectional nature of this study, the results are not definitive, and longitudinal studies are required to assess the association of GCF TACE levels with disease progression.
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ACKNOWLEDGMENTS
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This study was supported by the authors’ institutions.
Received for publication July 5, 2007.
Revision received November 21, 2007.
Accepted for publication December 14, 2007.
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Journal of Dental Research, Vol. 87, No. 3,
273-277 (2008)
DOI: 10.1177/154405910808700311
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ABSTRACT
INTRODUCTION