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

Grant number: 18/02323-5
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): October 01, 2019
Effective date (End): August 31, 2022
Field of knowledge:Biological Sciences - Physiology - Physiology of Organs and Systems
Principal Investigator:Cecilia Helena de Azevedo Gouveia
Grantee:Bianca Neofiti Papi
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

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 Beta2-adrenoceptors (Beta2-AR) expressed in osteoblasts, and that the gene inactivation of Beta2-AR in mice results in a phenotype of High Bone Mass (HBM). Studies by our group showed that ±2 adrenoceptors (±2-AR) also mediate actions of the SNS in the skeleton and that there is an interaction between TH and the ±2 adrenoceptors signaling pathway to regulate bone mass. Recenly, we found that Beta2-AR-/- are resistant to the deleterious effects of thyrotoxicosis in the skeleton, 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 also involves the Beta2 adrenoceptor signaling pathway. However, it is still not clear whether the actions of the SNS and its interaction with TH occur directly in the skeleton. The present study aims to investigate if TH interacts with the Beta2-AR signaling pathway, 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 Beta2-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 present study will contribute to the understanding of the mechanisms of action of TH to modulate bone remodeling and osteoblast biology. (AU)