TY - JOUR
T1 - The cannabinoid CB1 receptor regulates bone formation by modulating adrenergic signaling
AU - Tam, Joseph
AU - Trembovler, Victoria
AU - Di Marzo, Vincenzo
AU - Petrosino, Stefania
AU - Leo, Gabriella
AU - Alexandrovich, Alex
AU - Regev, Eran
AU - Casap, Nardy
AU - Shteyer, Arie
AU - Ledent, Catherine
AU - Karsak, Meliha
AU - Zimmer, Andreas
AU - Mechoulam, Raphael
AU - Yirmiya, Raz
AU - Shohami, Esther
AU - Bab, Itai
PY - 2008/1
Y1 - 2008/1
N2 - We have recently reported that in bone the cannabinoid CB1 receptor is present in sympathetic terminals. Here we show that traumatic brain injury (TBI), which in humans enhances peripheral osteogenesis and fracture healing, acutely stimulates bone formation in a distant skeletal site. At this site we demonstrate i) a high level of the main endocannabinoid, 2-arachidonoylglycerol (2-AG), and expression of diacylglycerol lipases, enzymes essential for 2-AG synthesis; ii) that the TBI-induced increase in bone formation is preceded by elevation of the 2-AG and a decrease in norepinephrine (NE) levels. The TBI stimulation of bone formation was absent in CB1-null mice. In wild-type animals it could be mimicked, including the suppression of NE levels, by 2-AG administration. The TBI- and 2-AG-induced stimulation of osteogenesis was restrained by the β-adrenergic receptor agonist isoproterenol. NE from sympathetic terminals is known to tonically inhibit bone formation by activating osteoblastic β2-adrenergic receptors. The present findings further demonstrate that the sympathetic control of bone formation is regulated through 2-AG activation of prejunctional CB1. Elevation of bone 2-AG apparently suppresses NE release from bone sympathetic terminals, thus alleviating the inhibition of bone formation. The involvement of osteoblastic CB2 signaling in this process is minimal, if any.
AB - We have recently reported that in bone the cannabinoid CB1 receptor is present in sympathetic terminals. Here we show that traumatic brain injury (TBI), which in humans enhances peripheral osteogenesis and fracture healing, acutely stimulates bone formation in a distant skeletal site. At this site we demonstrate i) a high level of the main endocannabinoid, 2-arachidonoylglycerol (2-AG), and expression of diacylglycerol lipases, enzymes essential for 2-AG synthesis; ii) that the TBI-induced increase in bone formation is preceded by elevation of the 2-AG and a decrease in norepinephrine (NE) levels. The TBI stimulation of bone formation was absent in CB1-null mice. In wild-type animals it could be mimicked, including the suppression of NE levels, by 2-AG administration. The TBI- and 2-AG-induced stimulation of osteogenesis was restrained by the β-adrenergic receptor agonist isoproterenol. NE from sympathetic terminals is known to tonically inhibit bone formation by activating osteoblastic β2-adrenergic receptors. The present findings further demonstrate that the sympathetic control of bone formation is regulated through 2-AG activation of prejunctional CB1. Elevation of bone 2-AG apparently suppresses NE release from bone sympathetic terminals, thus alleviating the inhibition of bone formation. The involvement of osteoblastic CB2 signaling in this process is minimal, if any.
KW - 2-arachidonoylglycerol
KW - Norepinephrine
KW - Sympathetic nervous system
KW - Traumatic brain injury
UR - http://www.scopus.com/inward/record.url?scp=38049132712&partnerID=8YFLogxK
U2 - 10.1096/fj.06-7957com
DO - 10.1096/fj.06-7957com
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C2 - 17704191
AN - SCOPUS:38049132712
SN - 0892-6638
VL - 22
SP - 285
EP - 294
JO - FASEB Journal
JF - FASEB Journal
IS - 1
ER -