Double disruption of α2A- and α2C-adrenoceptors results in sympathetic hyperactivity and high-bone-mass phenotype.
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.
Fonseca
Tatiana L
TL
Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
Jorgetti
Vanda
V
Costa
Cristiane C
CC
Capelo
Luciane P
LP
Covarrubias
Ambart E
AE
Moulatlet
Ana C
AC
Teixeira
Marilia B
MB
Hesse
Eric
E
Morethson
Priscilla
P
Beber
Eduardo H
EH
Freitas
Fatima R
FR
Wang
Charles C
CC
Nonaka
Keico O
KO
Oliveira
Ricardo
R
Casarini
Dulce E
DE
Zorn
Telma M
TM
Brum
Patricia C
PC
Gouveia
Cecilia H
CH
D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D001862:Bone Resorption / Q000097:blood / Q000150:complications / Q000235:genetics; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004958:Estradiol / Q000097:blood; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects; D006948:Hyperkinesis / Q000097:blood / Q000150:complications / Q000473:pathology*; D020738:Leptin / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009638:Norepinephrine / Q000097:blood; D009929:Organ Size / Q000187:drug effects; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects; D010641:Phenotype; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000473:pathology*; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein
D058647:Adrenergic alpha-2 Receptor Agonists; D020738:Leptin; D009419:Nerve Tissue Proteins; D018341:Receptors, Adrenergic, alpha-2; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein; D004958:Estradiol; D009638:Norepinephrine