Thyrotoxicosis Involves β2-Adrenoceptor Signaling to Negatively Affect Microarchitecture and Biomechanical Properties of the Femur
| Autor: | Vanda Jorgetti, Nathalia Juliana Nardelli Gonçalves, Cecilia H. A. Gouveia, Rudá Prestes e Albuquerque, Manuela Miranda-Rodrigues, Bianca Neofiti-Papi, Julio C.B. Ferreira, Patricia Chacur Brum |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Male
Sympathetic Nervous System Endocrinology Diabetes and Metabolism Gene Expression Bone remodeling Mice 0302 clinical medicine Endocrinology Cyclic AMP Femur Receptor Mice Knockout Triiodothyronine Estradiol Receptor Activator of Nuclear Factor-kappa B biology Chemistry ESTRÓGENOS Biomechanical Phenomena Resorption Thyrotoxicosis medicine.anatomical_structure RANKL 030220 oncology & carcinogenesis Female Bone Remodeling Signal Transduction medicine.medical_specialty Medullary cavity 030209 endocrinology & metabolism Cell Line 03 medical and health sciences Internal medicine medicine Animals Clenbuterol Adrenergic beta-2 Receptor Agonists Osteoblasts RANK Ligand Osteoprotegerin Estrogens X-Ray Microtomography medicine.disease Osteopenia Bone Diseases Metabolic biology.protein Cortical bone Receptors Adrenergic beta-2 |
| Zdroj: | Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP |
| ISSN: | 1557-9077 1050-7256 |
| DOI: | 10.1089/thy.2018.0259 |
| Popis: | Background: Thyrotoxicosis increases bone turnover, resulting in net bone loss. Sympathetic nervous system (SNS) activation, via β2-adrenoceptor (β2-AR) signaling, also has osteopenic effects. Because thyroid hormones (TH) interact with the SNS to regulate several physiological processes, we hypothesized that this interaction also occurs to regulate bone mass. Previous studies support this hypothesis, as α2-AR knockout (KO) mice are less susceptible to thyrotoxicosis-induced osteopenia. Here, we evaluated whether TH-SNS interactions in bone involve β2-AR signaling. Methods: Thyrotoxicosis was induced in 120-day-old female and male mice with β2-AR gene inactivation (β2-AR-/-) by daily treatment with supraphysiological doses of triiodothyronine (T3) for 12 weeks. The impact of thyrotoxicosis on femoral bone microarchitecture, remodeling, fracture risk, and gene expression of the receptor activator of nuclear factor-kappa-B (RANK)-RANK ligand (RANKL)-osteoprotegerin (OPG) pathway was evaluated. In addition, the effect of the β2-AR-specific agonist clenbuterol (CL) on cAMP accumulation was determined in osteoblastic (MC3T3-E1) cells treated with T3 and/or 17β-estradiol (E2). Results: Thyrotoxicosis negatively affected trabecular bone microarchitecture in wild-type (WT) females, but this effect was milder or nonexistent in β2-AR-/- animals, whereas the opposite was seen in males. T3 treatment increased the femoral RANKL/OPG mRNA ratio and the endosteal perimeter and medullary area of the diaphysis in WT females and males, but not in β2-AR-/- mice, suggesting that T3 promotes endosteal resorption in cortical bone, in a mechanism that involves β2-AR signaling. T3 treatment increased endocortical mineral apposition rate only in WT females but not in β2-AR-/- mice, suggesting that TH also induce bone formation in a β2-AR signaling-dependent mechanism. T3 treatment decreased femoral resistance to fracture only in WT females, but not in KO mice. E2 and CL similarly increased cAMP accumulation in MC3T3-E1 cells; whereas T3 alone had no effect, but it completely blocked E2-stimulated cAMP accumulation, suggesting that some T3 effects on bone may involve E2/cAMP signaling in osteoblasts. Conclusions: These findings sustain the hypothesis that T3 interacts with the SNS to regulate bone morphophysiology in a β2-AR signaling-dependent mechanism. The data also reveal sex as an important modifier of skeletal manifestations of thyrotoxicosis, as well as a modifier of the TH-SNS interactions to control bone microarchitecture, remodeling, and resistance to fracture. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|