Double disruption of α2A- and α2C-adrenoceptors results in sympathetic hyperactivity and high-bone-mass phenotype.
J Bone Miner Res
; 26(3): 591-603, 2011 Mar.
Article
em En
| MEDLINE
| ID: mdl-20814988
ABSTRACT
Evidence demonstrates that sympathetic nervous system (SNS) activation causes osteopenia via ß(2)-adrenoceptor (ß2-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 ß(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 ß(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 ß(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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Sistema Nervoso Simpático
/
Osso e Ossos
/
Deleção de Genes
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Receptores Adrenérgicos alfa 2
/
Hipercinese
Limite:
Animals
Idioma:
En
Revista:
J Bone Miner Res
Assunto da revista:
METABOLISMO
/
ORTOPEDIA
Ano de publicação:
2011
Tipo de documento:
Article
País de afiliação:
Brasil