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The cannabinoid CB1 receptor regulates bone formation by modulating adrenergic signaling

Joseph Tam^*, Victoria Trembovler, Vincenzo Di Marzo^¶, Stefania Petrosino^¶,#, Gabriella Leo^¶, Alex Alexandrovich, Eran Regev, Nardy Casap, Arie Shteyer, Catherine Ledent^**, Meliha Karsak, Andreas Zimmer, Raphael Mechoulam, Raz Yirmiya^||, Esther Shohami and Itai Bab^*,1

^* Bone Laboratory,

Department of Pharmacology,

Department of Oral and Maxillofacial Surgery, Hadassah School of Dental Medicine,

Department of Medicinal Chemistry and Natural Products, and

^|| Department of Psychology, Hebrew University of Jerusalem, Jerusalem, Israel;

^¶ Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Italy;

^# Dipartimento di Scienze Farmaceutiche, Università degli Studi di Salerno, Fisciano, Italy;

^** Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, Brussels, Belgium; and

Institute of Molecular Psychiatry, University of Bonn, Bonn, Germany

¹ Correspondence: Bone Laboratory, the Hebrew University of Jerusalem, Jerusalem 91120, Israel. E-mail: babi{at}cc.huji.ac.il

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.—Tam, J., Trembovler, V., Di Marzo, V., Petrosino, S., Leo, G., Alexandrovich, A., Regev, E., Casap, N., Shteyer, A., Ledent, C., Karsak, M., Zimmer, A., Mechoulam, R., Yirmiya, R., Shohami, E., Bab, I. The cannabinoid CB1 receptor regulates bone formation by modulating adrenergic signaling.

Key Words: 2-arachidonoylglycerol • norepinephrine • sympathetic nervous system • traumatic brain injury

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