Are alfa2C-adrenergic receptors functional in osteoclasts and do they directly mediate thyroid hormone effects in these cells?

• Grant number: 13/12477-6
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• Start date until: October 01, 2013
• End date until: September 30, 2014
• Field of knowledge: Biological Sciences - Physiology - General Physiology
• Principal Investigator: Cecilia Helena de Azevedo Gouveia
• Grantee: Marília Bianca Cruz Grecco Teixeira
• Supervisor: Deborah J. Veis Novack
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: University of Washington, United States

Abstract

One of the most interesting finds of the recent years is that bone remodeling is also under control of Sympathetic Nervous System (SNS). Evidences demonstrate that the SNS activation causes osteopenia via beta2-adrenoceptor (beta2-AR) signaling. In a recent study, we showed that female mice with chronic sympathetic hyperactivity due to double knockout of adrenoceptors that negatively regulate norepinephrine release, alpha2A-AR and alpha2C-AR (alpha2A/alpha2C-ARKO), present an unexpected and generalized phenotype of high bone mass with decreased bone resorption and increased bone formation, despite presenting intact beta2-AR. Furthermore, we found that these animals are resistant to the thyrotoxicosis-induced osteopenia. These findings suggest that beta2-AR is not the single adrenoceptor involved in bone mass regulation and show that alpha2-AR signaling may also mediate the SNS and thyroid hormone (TH) actions in the skeleton. To further investigate the participation of alpha2-ARs and its possible interaction with TH in the regulation of bone physiology and structure, we are evaluating the bone phenotype of alpha2CAR KO mice (alpha2CAR-/-) and the effect of TH on the skeleton of these animals. We found that ±2CAR-/- mice present lower trabecular bone volume (BV/TV) in the femur and higher BV/TV in the vertebra. We also observed that alpha2CAR-/- mice are less sensitive to the thyrotoxicosis-induced osteopenia. These findings suggest that the SNS has heterogeneous effects in the skeleton and reinforce the hypothesis that açpha2-AR signaling may also mediate the SNS and TH actions in the skeleton. To confirm these hypotheses, it is now necessary to evaluate how WT and alpha2-AR KO bone cells behave and respond to alpha adrenergic receptor agonists and antagonists in the presence and absence of TH. The aim of the present study is to investigate if alpha 2C-adrenergic receptors are functional in osteoclast precursors and osteoclasts and if they directly mediate thyroid hormone effects in these cells. (AU)