TY - JOUR
T1 - Double disruption of α2A- and α2C -adrenoceptors results in sympathetic hyperactivity and high-bone-mass phenotype
AU - Fonseca, Tatiana L.
AU - Jorgetti, Vanda
AU - Costa, Cristiane C.
AU - Capelo, Luciane P.
AU - Covarrubias, Ambart E.
AU - Moulatlet, Ana C.
AU - Teixeira, Marilia B.
AU - Hesse, Eric
AU - Morethson, Priscilla
AU - Beber, Eduardo H.
AU - Freitas, Fatima R.
AU - Wang, Charles C.
AU - Nonaka, Keico O.
AU - Oliveira, Ricardo
AU - Casarini, Dulce E.
AU - Zorn, Telma M.
AU - Brum, Patricia C.
AU - Gouveia, Cecilia H.
PY - 2011/3
Y1 - 2011/3
N2 - Evidence demonstrates that sympathetic nervous system (SNS) activation causes osteopenia via β2-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, α2A-AR and α2C-AR (α2A/α2C-ARKO), present an unexpected and generalized phenotype of high bone mass with decreased bone resorption and increased formation. In α2A/α2C-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 β2-AR mRNA expression also was similar in KO and WT littermates, whereas α2A-, α2B- and α2C- AR mRNAs were detected in the tibia of WT mice and in osteoblast-like MC3T3-E1 cells. By immunohistochemistry, we detected α2A-, α2B-, α2C- and β2-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 α2-AR agonist clonidine and to the nonspecific α-AR antagonist phentolamine. These findings suggest that β2-AR is not the single adrenoceptor involved in bone turnover regulation and show that α2-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.
AB - Evidence demonstrates that sympathetic nervous system (SNS) activation causes osteopenia via β2-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, α2A-AR and α2C-AR (α2A/α2C-ARKO), present an unexpected and generalized phenotype of high bone mass with decreased bone resorption and increased formation. In α2A/α2C-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 β2-AR mRNA expression also was similar in KO and WT littermates, whereas α2A-, α2B- and α2C- AR mRNAs were detected in the tibia of WT mice and in osteoblast-like MC3T3-E1 cells. By immunohistochemistry, we detected α2A-, α2B-, α2C- and β2-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 α2-AR agonist clonidine and to the nonspecific α-AR antagonist phentolamine. These findings suggest that β2-AR is not the single adrenoceptor involved in bone turnover regulation and show that α2-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.
KW - adrenergic receptors
KW - bone mass
KW - bone metabolism
KW - SNS
KW - Sympathetic hyperactivity
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U2 - 10.1002/jbmr.243
DO - 10.1002/jbmr.243
M3 - Article
C2 - 20814988
AN - SCOPUS:79951846045
SN - 0884-0431
VL - 26
SP - 591
EP - 603
JO - Journal of Bone and Mineral Research
JF - Journal of Bone and Mineral Research
IS - 3
ER -