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Study of B4 leukotriene involvement in controlling angiogenesis process osteogenesis coupled to the arthritic condition.

Abstract

Angiogenesis and osteogenesis are coupled during skeletal development. Endothelial cell and bone cells secrete various factors that help them to communicate with each other to establish proper bone homeostasis. Leukotriene B4 (LTB4) is a bone degrading factor, secreted in arthritis like inflammatory conditions by various cell types including bone cells such as osteoblast and osteoclast. Although most of knowledge is based on LTs-mediated osteoclasts bone resorbing activity, mechanism of action of LTB4 from osteoblast to drive osteoclastogenesis is unknown, especially the contribution of endothelial cells. Endothelial cells express receptor for LTB4 and its binding increases Vascular endothelial growth factor (VEGF)-mediated angiogenesis. VEGF is a secreted factor known to induce osteoblast differentiation and Receptor activator of nuclear factor kappa-B ligand (RANKL) expression and is directly induces the osteoclastogenesis. We hypothesized that endothelial VEGF could be a target for bone cells derived LTB4 to increase osteoclastogenesis in rheumatoid arthritis condition. So aim of this study is to evaluate the involvement of LTB4 in the crosstalk between endothelial and bone cells dependent on VEGF during skeletogenesis. For this, primary bone vascular endothelial cells will be treated with LTB4 and the VEGF expression as well as its direct or indirect (dependent on osteoblast) effect on osteoclastogenesis will be determined. The contribution of osteoblast and osteoclast as source of LTB4 to induce over expression of VEGF will be also evaluated through co-culture experiments. The results from in vitro experiments will be further validated by using arthritis mouse model in vivo. After treating the arthritis mice with BLT1 antagonist, the levels of VEGF and bone resorption marker CTX in serum will be quantified. Studying the underappreciate role of LTB4 in the VEGF-mediated endothelial and bone cells crosstalk might bring new insights of therapeutical targets for bone loss in arthritis-like conditions. (AU)

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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)
SANTESSO, MARIANA R.; OLIVEIRA, FLAVIA A.; TOKUHARA, CINTIA K.; OLIVEIRA, GABRIELA S. N.; LEVY, FLAVIA M.; ANTONIO, LIGIA S.; BUZALAF, MARILIA A. R.; OLIVEIRA, RODRIGO C. Fluoride effects on cell viability and ENaC expression in kidney epithelial cells. TOXICOLOGY MECHANISMS AND METHODS, JUN 2021. Web of Science Citations: 0.

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