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

• Grant number: 19/16067-3
• Support Opportunities: Regular Research Grants
• Start date: September 01, 2020
• End date: August 31, 2023
• Field of knowledge: Health Sciences - Dentistry - Oral and Maxillofacial Surgery
• Principal Investigator: Mariza Akemi Matsumoto
• Grantee: Mariza Akemi Matsumoto
• Host Institution: Faculdade de Odontologia (FOA). Universidade Estadual Paulista (UNESP). Campus de Araçatuba. Araçatuba , SP, Brazil
• Associated researchers: Antonio Hernandes Chaves Neto ; Claudia Cristina Biguetti ; Edilson Ervolino ; Walid D Fakhouri
• Associated scholarship(s): 21/03814-5 - Influence of nitrogenous bisphosphonates (BPns) on inflammatory and endocrine factors: bases for understanding the pathophysiology of osteonecrosis of the jaws related to the use of BPns, BP.TT

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)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

MAHMOUD, RAMEZ H.; BIGUETTI, CLAUDIA C.; SIMIONATO, GUSTAVO B.; CUSTODIO, ISABELA C.; SILVA, RAQUEL B. P.; DUARTE, MARCO A. H.; FAVERANI, LEONARDO P.; ERVOLINO, EDILSON; FAKHOURI, WALID D.; MATSUMOTO, MARIZA A.. Alveolar socket healing in 5-lipoxygenase knockout aged female mice treated or not with high dose of zoledronic acid. SCIENTIFIC REPORTS, v. 11, n. 1, OCT 1 2021. (19/16067-3, 18/19409-0)

SIMIONATO, GUSTAVO BARONI; DA SILVA, ANA CLAUDIA RODRIGUES; DE OLIVA, ANDRE HERGESEL; FURQUIM, ELISA MARA DE ABREU; COUTO, MAIRA CRISTINA RONDINA; SHINOHARA, ANDRE LUIS; BIGUETTI, CLAUDIA CRISTINA; MATSUMOTO, MARIZA AKEMI. Lack of 5-lipoxygenase in intramembranous and endochondral 129Sv mice skeleton and intramembranous healing. ARCHIVES OF ORAL BIOLOGY, v. 131, NOV 2021. (18/19406-0, 19/16067-3, 18/14488-9)

RIBEIRO, KIM HENDERSON CARMO; DA SILVA, RAQUEL BARROSO PARRA; ROSENO, ANA CAROLYNA BECHER; BARRETO, ANA JULIA MORENO; BACELAR, ANA CAROLINA ZUCON; ERVOLINO, EDILSON; DUARTE, MARCO ANTONIO HUNGARO; FAKHOURI, WALID D.; CHAVES-NETO, ANTONIO HERNANDES; BIGUETTI, CLAUDIA CRISTINA; et al. Dose-response effect of Montelukast on post-extraction dental socket repair and skeletal phenotype of mice. ODONTOLOGY, v. 111, n. 4, p. 13-pg., 2023-03-15. (19/16067-3)