Assessment of Vascular Endothelial Growth Factor and Matrix Metalloproteinase-9 in the Periodontium of Rats Treated With Atorvastatin

• Localización: Journal of periodontology, ISSN 0022-3492, Nº. 1, 2014, págs. 178-187
• Idioma: inglés
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• Resumen

  • Background: The aim of this study is to examine, for the first time, the role of systemic and local atorvastatin application on periodontium using histomorphometric and immunohistochemical analysis during and after experimental periodontitis induction with or without the presence of microbial dental biofilm.

    Methods: One hundred ten male Wistar rats were used. Silk ligatures were placed around the cervical area of the mandibular first molars; rats in the healthy control group received no ligatures (n = 10). In experimental periodontitis groups (n = 90), systemic and local atorvastatin and saline were administered in three different periods; the control periodontitis group (n = 10) received no treatment. Histomorphometric analysis, which included alveolar bone area, alveolar bone level, and attachment loss, and immunohistochemical analysis, which included immunoreactivity of vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP)-9, were performed after the rats were sacrificed at the end of the experimental procedure.

    Results: There was a greater increase in alveolar bone area and VEGF immunoreactivity, as well as a greater decrease in alveolar bone and attachment loss and MMP-9 immunoreactivity, with systemic and local atorvastatin application during and after induction of experimental periodontitis. Local atorvastatin application showed better results on periodontium with regard to alveolar bone findings.

    Conclusions: Systemic and local atorvastatin application showed beneficial effects on periodontium during and after induction of experimental periodontitis. Within the limits of this study, it can be concluded that atorvastatin, which is used for hypercholesterolemia treatment, can also be used as a protective and therapeutic agent for periodontal disease.

    Periodontitis, an oral infectious disease caused by specific microorganisms or groups of microorganisms, is characterized by clinical attachment loss (AL), alveolar bone resorption, periodontal pocketing, and gingival inflammation.1 Microorganisms and their products lead to the recruitment of inflammatory cells, generation of cytokines, release of proteolytic enzymes, and activation of osteoclasts. Thus, periodontal tissue breakdown, a characteristic feature of periodontitis, occurs.2 Various regenerative procedures such as guided tissue regeneration, bone grafting, application of enamel matrix derivative, various polypeptide growth factors, and combinations of these therapies have been used for treatment of the destroyed periodontal tissues.3 Although these techniques usually result in successful clinical outcomes, due to some practical difficulties and some mechanisms (biological and physicochemical characteristics of biomaterials and individual components), they have achieved limited success in the amount of periodontal architecture formed.3 Statins inhibit cholesterol synthesis in the liver. These agents block the conversion of 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate by blocking 3-hydroxy-3-methylglutaryl-coenzyme A reductase, which is the rate-limiting enzyme.4,5 In addition to cholesterol-lowering activity, statins have pleiotropic effects, including promotion of vasculogenesis, expression of bone anabolic factors such as bone morphogenetic protein (BMP)-2, and anti-inflammatory, antioxidant, and immunomodulatory effects.5 The anabolic effect of statins on bone is realized in two ways: 1) direct activation of BMP and 2) inhibition of bone resorption by decreasing the expression of receptor activator of nuclear factor ?B ligand and cathepsin K.6,7 Mundy et al.8 first reported that statins stimulated bone formation in rodents and increased production of BMP-2 in bone cells. The use of statins such as simvastatin and atorvastatin has shown significant improvement in periodontal parameters (probing depth [PD], clinical attachment level [CAL], tooth mobility, and intrabony defect fill) in clinical studies and beneficial effects on alveolar bone loss (ABL) and bone growth in animal studies.9-14 The above observations lead to the speculation that statin application could be beneficial for the periodontium by anti-inflammatory action.

    Vascular endothelial growth factor (VEGF) is a multifunctional angiogenic growth factor, relatively specific for endothelial cells, which is expressed by many cells in both physiologic and pathologic processes. VEGF regulates vasculogenesis and angiogenesis, increases microvascular permeability, stimulates endothelial cell growth and differentiation, and induces migration of endothelial cells, monocytes, and osteoblasts.15-17 Additionally, current studies suggest that VEGF also has an important role in the regulation of periodontal disease.18-20 Matrix metalloproteinases (MMPs) are a family of metal-dependent proteolytic enzymes that degrade the proteinaceous components of the extracellular matrix and cleave signaling proteins.21 The regulation of MMP activity occurs through transcriptional regulation of MMP genes, precursor activation, differences in substrate specificity, and MMP inhibitors (a2-macroglobulin and tissue inhibitors of MMPs).22 MMPs participate in both physiologic (bone remodeling, wound healing, angiogenesis, apoptosis) and pathologic (cardiovascular disease, arthritis, cancer, periodontal disease) processes.23 Evidence indicates that the amount of MMP-9 (gelatinase B) in gingival crevicular fluid is increased during periodontal disease and reduced after periodontal treatment.24-28 As has been reported, both VEGF and MMP-9 play important roles in inflammation and wound healing; furthermore, neutrophil-derived MMP-9 was identified as a factor during angiogenic processes along with VEGF.29,30 Although VEGF and MMP-9 have been widely studied in several diseases as well as periodontal disease, no data are available regarding the results of statin application on periodontium by detecting these markers.

    Although many recent clinical and experimental works have concentrated on systemic and local statin treatments in periodontal disease, several issues still await clarification.9-14 As periodontitis is an inflammatory and bone-destructive disease, and microbial dental biofilm accumulation is the primary etiologic factor for periodontal disease, detection of the effect of statin application may be useful owing to its anti-inflammatory action for periodontal disease prevention and therapy in the presence and absence of microbial dental biofilm. The aim of this study is to examine, for the first time, the role of systemic and local atorvastatin application on periodontium using histomorphometric and immunohistochemical analysis during and after experimental periodontitis induction with or without the presence of microbial dental biofilm.