Reduced ADAM8 levels upon non-surgical periodontal therapy in patients with chronic periodontitis

Highlights

• GCF ADAM8 levels were higher in chronic periodontitis than in gingivitis.

• GCF ADAM8 levels were decreased after treatment only in the periodontitis group.

• Likewise, the severity of periodontitis was clinically reduced after treatment.

• Correlations between ADAM8 levels and clinical parameters in chronic periodontitis.

Abstract

Objective

To determine effect of non-surgical periodontal treatment on a disintegrin and metalloproteinase 8 (ADAM8) levels in gingival crevicular fluid (GCF) of patients with chronic periodontitis (CP) in comparison with those of patients with gingivitis and to find correlations between ADAM8 levels and clinical parameters.

Design

Twenty-two and eleven patients with CP and gingivitis, respectively, were examined for four clinical parameters, probing depth, clinical attachment level, gingival and plaque indices. GCF from the selected gingivitis or periodontitis sites with distinct severities was sampled by Periopaper strips. The non-surgical treatments, including scaling and/or root planing and oral hygiene instruction, were provided for all patients. Clinical measurements and GCF sampling were repeated at three months after the treatments. ADAM8 concentrations were analyzed by ELISA and normalized by GCF volumes or total protein amounts.

Results

All patients exhibited significant improvement of almost every clinical parameter after treatment, whereas the median ADAM8 concentrations were significantly decreased at the moderate and severe periodontitis sites of patients with CP (p < 0.05). Moreover, the significantly positive correlations between ADAM8 concentrations and four clinical parameters were found in both moderate and severe groups (p < 0.05).

Conclusion

ADAM8 concentrations were decreased by non-surgical periodontal therapy in patients with chronic periodontitis at the moderate and severe sites and were correlated with four clinical parameters, implying that GCF ADAM8 levels reflect inflammatory and bone-resorbing activities in the periodontal pocket.

Introduction

The pathogenesis of chronic periodontitis (CP) is caused by overwhelming host immune responses to persistent infections from periodontopathogenic microorganisms within the dental plaque (Cekici, Kantarci, Hasturk, & Van Dyke, 2014). Advanced progression of this disease can lead to damage of tooth supporting structures and eventual tooth loss. Several clinical manifestations and parameters as well as dental radiography are commonly used as a gold standard to define the stages of CP depending on the amounts of alveolar bone destruction and attachment loss. Moreover, a number of inflammatory molecules detected in gingival crevicular fluid (GCF), such as interleukin (IL)-1, IL-6, IL-8, tumor necrosis factor (TNF)-α along with other inflammation-related molecules, like matrix metalloproteinase (MMP)-3, MMP-8 and receptor activator of nuclear factor kappaB ligand, are proposed to be useful biomarkers to indicate an active state of CP (Hernández et al., 2011; Ohlrich, Cullinan, & Seymour, 2009; Toyman et al., 2015). Besides MMP-3 and MMP-8, our previous study and the others have demonstrated a significant elevation of the other two members of the metzincin superfamily of Zn²⁺-dependent proteases, including a disintegrin and metalloproteinase (ADAM) 8 and ADAM17 or tumor necrosis factor-α (TACE), in GCF from periodontitis lesions (Bostanci et al., 2008; Elavarasu et al., 2015; Khongkhunthian et al., 2013). Expression of ADAM8 is also enhanced in the synovial membrane and pannus tissues of patients with rheumatoid arthritis (Ainola et al., 2009), indicating a significant role of ADAM8 in inflammation-induced bone loss in rheumatoid arthritis.

ADAM8 is a type I transmembrane glycoprotein that is mostly expressed on the cell membrane of hematopoietic cells, including neutrophils, monocytes, eosinophils, dendritic cells and B lymphocytes (Richens et al., 2007; Yoshiyama, Higuchi, Kataoka, Matsuura, & Yamamoto, 1997). However, some other non-immune cells, including bronchial and vascular smooth muscle cells, bronchial epithelial cells and human osteoarthritic chondrocytes, have been previously shown to express ADAM8 (Chiba et al., 2009; King et al., 2004; Zack et al., 2009). Particularly relevant to this study, expression of ADAM8 is localized in the epithelium of gingival biopsies from patients with CP and is up-regulated in cultured gingival epithelial cells upon challenges with Fusobacterium nucleatum (Aung et al., 2017). ADAM8 mainly functions to cleave various membrane proteins relating to host immune system, including l-selectin, P-selectin glycoprotein ligand-1, CD23, neural ectodomain of close homologue of L1 and TNF-α receptor 1 (Bartsch et al., 2010; Fourie, Coles, Moreno, & Karlsson, 2003; Gómez-Gaviro et al., 2007; Naus et al., 2004; Nishimura et al., 2015). ADAM8 also plays a role in osteoclastogenesis, especially at the late stage of osteoclast differentiation in cultured mouse bone marrow cells (Choi, Han, & Roodman, 2001). Furthermore, an in vivo study has shown decreased bone volume while increased trabecular space in transgenic mice with ADAM8 overexpression (Ishizuka et al., 2011). Taken together, all of these studies have pointed towards a pivotal role of ADAM8 in both host immunity and osteoclastogenesis.

Since CP, a bone destructive disease driven by excessive host immune responses, results from enhanced bone resorption by increased osteoclast number and activity (Cekici et al., 2014), it was, therefore, logical to hypothesize that raised ADAM8 levels in GCF of patients with CP would be decreased after periodontal treatment and the ADAM8 levels would be positively correlated with four clinical parameters, including probing depth (PD), clinical attachment level (CAL), gingival index (GI) and plaque index (PI), as a gold standard. The aims of this study were to determine effect of non-surgical periodontal therapy on GCF ADAM8 levels of patients with CP in comparison with those of patients with gingivitis and to find correlations between ADAM8 levels and the four clinical parameters.