Global Disruption of alpha 2A Adrenoceptor Barely Affects Bone Tissue but Minimizes the Detrimental Effects of Thyrotoxicosis on Cortical Bone

Author(s)

Martins, Gisela M. ^{[1, 2]} ; Teixeira, Marilia B. C. G. ^[1] ; Silva, V, Marcos ; Neofiti-Papi, Bianca ^{[3, 4]} ; Miranda-Rodrigues, Manuela ^{[5, 4]} ; Brum, Patricia C. ^[6] ; Gouveia, Cecilia H. A. ^{[3, 4]}

Affiliation

^[1] Univ Sao Paulo, Inst Biomed Sci, Dept Anat, Sao Paulo - Brazil

^[2] Univ Fed Espirito Santo, Dept Morphol, Vitoria - Brazil

^[3] Univ Sao Paulo, Sch Med, Sao Paulo - Brazil

^[4] Silva, Marcos, V, Univ Sao Paulo, Inst Biomed Sci, Dept Anat, Sao Paulo - Brazil

^[5] Univ Western Ontario, London, ON - Canada

^[6] Univ Sao Paulo, Sch Phys Educ & Sport, Sao Paulo - Brazil

• Document type: Journal article
• Source: FRONTIERS IN ENDOCRINOLOGY; v. 9, AUG 28 2018.
• Web of Science Citations: 1

Abstract

Evidence shows that sympathetic nervous system (SNS) activation inhibits bone formation and activates bone resorption leading to bone loss. Because thyroid hormone (TH) interacts with the SNS to control several physiological processes, we raised the hypothesis that this interaction also controls bone remodeling. We have previously shown that mice with double-gene inactivation of alpha 2A- and -adrenoceptors (alpha 2A/2C-AR(-)(/-)) present high bone mass (HBM) phenotype and resistance to thyrotoxicosis-induced osteopenia, which supports a TH-SNS interaction to control bone mass and suggests that it involves alpha 2-AR signaling. Accordingly, we detected expression of alpha 2A-AR, alpha 2B-AR and alpha 2C-AR in the skeleton, and that triiodothyronine (T3) modulates alpha 2C-AR mRNA expression in the bone. Later, we found that mice with single-gene inactivation of alpha 2C-AR (alpha 2C-AR(-)(/-)) present low bone mass in the femur and HBM in the vertebra, but that both skeletal sites are resistant to TH-induce osteopenia, showing that the SNS actions occur in a skeletal site-dependent manner, and that thyrotoxicosis depends on alpha 2C-AR signaling to promote bone loss. To further dissect the specific roles of alpha 2-AR subtypes, in this study, we evaluated the skeletal phenotype of mice with single-gene inactivation of alpha 2A-AR (alpha 2A-AR(-/)(-)), and the effect of daily treatment with a supraphysiological dose of T3, for 4 or 12 weeks, on bone microarchitecture and bone resistance to fracture. Micro-computed tomographic (mu CT) analysis revealed normal trabecular and cortical bone structure in the femur and vertebra of euthyroid alpha(2)(A)-AR(-/-) mice. Thyrotoxicosis was more detrimental to femoral trabecular bone in alpha 2A-AR(-/-) than in WT mice, whereas this bone compartment had been previously shown to present resistance to thyrotoxicosis in alpha 2C-AR(-/- )mice. Altogether these findings reveal that TH excess depends on alpha 2C-AR signaling to negatively affect femoral trabecular bone. In contrast, thyrotoxicosis was more deleterious to femoral and vertebral cortical bone in WT than in alpha 2A-AR(-/-) mice, suggesting that alpha 2A-AR signaling contributes to TH actions on cortical bone. These findings further support a TH-SNS interaction to control bone physiology, and suggest that alpha 2A-AR and alpha 2C-AR signaling pathways have key roles in the mechanisms through which thyrotoxicosis promotes its detrimental effects on bone remodeling, structure and resistance to fracture. (AU)

• FAPESP's process: 17/27023-1 - 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.
• Grantee: Cecilia Helena de Azevedo Gouveia
• Support type: Regular Research Grants
• FAPESP's process: 15/10671-5 - Local interaction of thyroid hormone with the alfa 2-adrenoceptor system on Endocondral bone development and growth: an evaluation in organ culture and chondrocyte primary culture
• Grantee: Cecilia Helena de Azevedo Gouveia
• Support type: Regular Research Grants