Premium
Double disruption of α 2A ‐ and α 2C ‐adrenoceptors results in sympathetic hyperactivity and high‐bone‐mass phenotype
Author(s) -
Fonseca Tatiana L,
Jorgetti Vanda,
Costa Cristiane C,
Capelo Luciane P,
Covarrubias Ambart E,
Moulatlet Ana C,
Teixeira Marilia B,
Hesse Eric,
Morethson Priscilla,
Beber Eduardo H,
Freitas Fatima R,
Wang Charles C,
aka Keico O,
Oliveira Ricardo,
Casarini Dulce E,
Zorn Telma M,
Brum Patricia C,
Gouveia Cecilia H
Publication year - 2011
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1002/jbmr.243
Subject(s) - phenotype , sympathetic nervous system , medicine , endocrinology , biology , genetics , blood pressure , gene
Evidence demonstrates that sympathetic nervous system (SNS) activation causes osteopenia via β 2 ‐adrenoceptor (β2‐AR) signaling. Here we show that female mice with chronic sympathetic hyperactivity owing to double knockout of adrenoceptors that negatively regulate norepinephrine release, α 2A ‐AR and α 2C ‐AR (α 2A /α 2C ‐ARKO), present an unexpected and generalized phenotype of high bone mass with decreased bone resorption and increased formation. In α 2A /α 2C ‐ARKO versus wild‐type (WT) mice, micro–computed tomographic (µCT) analysis showed increased, better connected, and more plate‐shaped trabeculae in the femur and vertebra and increased cortical thickness in the vertebra, whereas biomechanical analysis showed increased tibial and femoral strength. Tibial mRNA expression of tartrate‐resistant acid phosphatase (TRACP) and receptor activator of NF‐κB (RANK), which are osteoclast‐related factors, was lower in knockout (KO) mice. Plasma leptin and brain mRNA levels of cocaine amphetamine–regulated transcript (CART), which are factors that centrally affect bone turnover, and serum levels of estradiol were similar between mice strains. Tibial β 2 ‐AR mRNA expression also was similar in KO and WT littermates, whereas α 2A ‐, α 2B ‐ and α 2C ‐AR mRNAs were detected in the tibia of WT mice and in osteoblast‐like MC3T3‐E1 cells. By immunohistochemistry, we detected α 2A ‐, α 2B ‐, α 2C ‐ and β 2 ‐ARs in osteoblasts, osteoclasts, and chondrocytes of 18.5‐day‐old mouse fetuses and 35‐day‐old mice. Finally, we showed that isolated osteoclasts in culture are responsive to the selective α 2 ‐AR agonist clonidine and to the nonspecific α‐AR antagonist phentolamine. These findings suggest that β 2 ‐AR is not the single adrenoceptor involved in bone turnover regulation and show that α 2 ‐AR signaling also may mediate the SNS actions in the skeleton. © 2010 American Society for Bone and Mineral Research. © 2011 American Society for Bone and Mineral Research.