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Influence of nitrogen-containing bisphosphonates (n-BPs) on inflammatory and endocrine factors: basis for the comprehension of osteonecrosis of the jaws related to nBPs pathophysiology

Abstract

The severity of nitrogen containing bisphosphonate-related osteonecrosis of the jaws (BRONJ) has heading basic sciences researches for the understanding of their pathophysiology and preventive methods. In this context, there is an increasing benefit in the comprehension of the exact role of the nitrogen containing bisphosphonate (nBPs) on bone metabolism and its influence on other inter related systems, such as the immunological and endocrine ones, which remain poorly explored. In this way, the present study aims to investigate the influence of nBPs on the inflammatory factors, with emphasis on eicosanoids, and endocrine, with emphasis on vitamin D, under experimental conditions. In order to achieve these goals, this project will analyze the enzymes of the metabolism of arachidonic acid (AA), their correlated mediators and levels of vitamin D during the development of BRONJ lesions in a genetically modified animal model, 5-lipoxygenase knockout (5-LO) under the effects of a pharmacological inhibitor of LTB4 receptor post-tooth extraction using a high potency nBP. Male 129Sv mice (WT and genetically modified, knockout for 5-LO - 5-LOKO) 12-16 weeks old, will be divided in groups according to the treatment: C - WT and 5-LOKO - 0.9% saline solution IP, WT-ZL - 250¼g/Kg every three days of ZL IP, and WT-MTK - montelukast, 2mg/Kg/day, by mouth. The preference for 129Sv inbreed is due the fact that these animals present a robust bone phenotype and their 5-LOKO variant make their skeleton even denser, similar to the WT animals under nBP treatment; however, without the side effects of the medication. Experimental periods will be set at day 21 after the surgeries, when blood will be collected and the right maxillae will be removed in order to undergo investigation of serum levels of vitamin D, calcium, phosphate, alkaline phosphatase, and total TRACP using quimioluminescence immuno assays and colorimetric method, analysis of bone microarchitecture of the healing sockets under microcomputed tomography (microCT), histopathology, and histomorphometry using the histological slices stained with hematoxilyn and eosin and Goldner trichrome, collagenous matrix investigation using slices stained with Picrosirius-red and analyzed under polarized light microscopy, immunohistochemistry and ELISA for the detection of bone and inflammatory targets. The data obtained will be treated using statistical tests considering p<0.05. (AU)