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In vitro evaluation of the interaction of thyroid hormone with the sympathetic nervous system, via alpha 2 and beta 2 adrenergic receptors, in the bone tissue and in osteoblasts

Grant number: 17/27023-1
Support type:Regular Research Grants
Duration: May 01, 2018 - April 30, 2020
Field of knowledge:Biological Sciences - Physiology
Principal Investigator:Cecilia Helena de Azevedo Gouveia
Grantee:Cecilia Helena de Azevedo Gouveia
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

It is well known that thyroid hormone (TH) is critical to bone development and metabolism, however, the mechanisms through which TH regulates these processes are poorly understood. Recently, the sympathetic nervous system (SNS) was identified as a potent regulator of bone metabolism. A series of studies showed that the action of the SNS are mediated by B2-adrenoceptors (B2-AR) expressed in osteoblasts, and that the gene inactivation of B2-AR in mice results in a phenotype of high bone mass (HBM). Studies by our group showed that alfa 2 adrenoceptors (a2-AR) mediate actions of the SNS in the skeleton. We identify the presence of a2A, a2B, and a2C adrenoceptors (a2A-AR, a2B-AR, and a2C-AR, respectively) in the main skeletal cells of mice, the osteoblasts, osteocytes, osteoclasts and chondrocytes. In addition, we found that mice with gene inactivation of both a2A-AR and a2C-AC (a2A/C-AR-/-) present a phenotype of high bone mass and are resistant to the thyrotoxicosis-induced osteopenia. On the other hand, mice with isolated inactivation of a2C-AR (a2C-AR-/-) show a low bone mass phenotype in the femur and high bone mass in the spine, which reveals heterogenic actions of a2 adrenergic signaling in the skeleton. Nevertheless, a2C-AR-/- mice are also resistant to the thyrotoxicosis-induced osteopenia in both skeletal sites (femur and vertebrae). We also found that B2-AR-/- are resistant to the deleterious effects of thyrotoxicosis, especially regarding to the endosteal resorption of the cortical bone, which reinforces the hypothesis that there is an TH-SNS interaction to regulate bone mass, suggesting that this interaction involves both a2 and B2 adrenoceptors signaling pathways. However, it is still not clear whether the actions of the SNS and its interaction with TH occur directly in the skeleton. Therefore, the present study aims to investigate if a2A-AR and a2C-AR have direct effects, i.e., local actions, in bone remodeling and in the biology of osteoblasts; in addition to evaluate whether TH interacts with a2A-AR, a2C-AR and/or B2-AR signaling pathways, locally in the bone tissue and in osteoblasts, to regulate these processes. For this purpose, an organ culture system of femurs and tibias, and a system of primary culture of osteoblasts derived from a2A-/-, a2C-AR-/- and B2-AR-/- mice will be established. The organ cultures will be used for the bone remodeling studies, through the analysis of the expression of genes related to bone metabolism. The primary cultures of osteoblasts will be established from the calvaria of neonate mice, and will be used for the study of the biology of osteoblasts, through the evaluation proliferation, differentiation and activity of these cells. The findings of this study may clarify the mechanisms through which TH and the SNS modulate bone remodeling and osteoblast biology. (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)
MARTINS, GISELA M.; TEIXEIRA, MARILIA B. C. G.; SILVA, V, MARCOS; NEOFITI-PAPI, BIANCA; MIRANDA-RODRIGUES, MANUELA; BRUM, PATRICIA C.; GOUVEIA, CECILIA H. A. Global Disruption of alpha 2A Adrenoceptor Barely Affects Bone Tissue but Minimizes the Detrimental Effects of Thyrotoxicosis on Cortical Bone. FRONTIERS IN ENDOCRINOLOGY, v. 9, AUG 28 2018. Web of Science Citations: 0.

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