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First published on June 13, 2006; DOI: 10.1124/mol.106.026435

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Received for publication May 9, 2006.
Revised June 8, 2006.
Accepted for publication June 13, 2006.

Involvement of Neuronal Cannabinoid Receptor, CB1, in Regulation of Bone Mass and Bone Remodeling

Joseph Tam 1, Orr Ofek 2, Ester Fride 3, Catherine Ledent 4, Yankel Gabet 2, Ralph Muller 5, Andreas Zimmer 6, Ken Mackie 7, Raphael Mechoulam 8, Esther Shohami 9, Itai Bab 2*

1 Bone laboratory, the Hebrew University of Jerusalem, Jerusalem 91120, Israel 2 Bone Laboratory, the Hebrew University of Jerusalem, Jerusalem 91120, Israel 3 Department of Behavioral Sciences, College of Judea and Samaria, Ariel 44837, Israel 4 Institut de Recherche Interdisciplinaire en Biologie Humaine et Moleculaire (I.R.I.B.H.M.), U 5 Institute for Biomedical Engineering, Swiss Federal Institute of Technology (ETH) and Univers 6 Laboratory of Molecular Neurobiology, Department of Psychiatry, University of Bonn, 53105 Bon 7 Departments of Anesthesiology and Physiology and Biophysics, University of Washington, Seattl 8 Department of Medicinal Chemistry and Natural Products, the Hebrew University of Jerusalem, Jerusale 9 Department of Pharmacology, the Hebrew University of Jerusalem, Jerusalem 91120, Israel

* Address correspondence to: E-mail: babi{at}cc.huji.ac.il

Abstract

Recently, the CB1 cannabinoid receptor was implicated in the regulation of bone remodelling and bone mass. A high bone mass (HBM) phenotype was reported in CB1-null mice generated on a CD1 background (CD1CB1-/- mice). By contrast, our preliminary studies in cb1-/- mice, backcrossed to C57Bl/6J mice (C57CB1-/- mice), revealed low bone mass (LBM). We therefore analyzed CB1 expression in bone and compared the skeletons of sexually mature C57CB1-/- and CD1CB1-/- mice in the same experimental setting. CB1 mRNA is weakly expressed in osteoclasts and immunoreactive CB1 is present in sympathetic neurons, close to osteoblasts. In addition to their LBM, male and female C57CB1-/- mice exhibit decreased bone formation rate and increased osteoclast number. The skeletal phenotype of the CD1CB1-/- mice shows a gender disparity. Females have normal trabecular bone with a slight cortical expansion, whereas male CD1CB1-/- animals display a HBM phenotype. Surprisingly, bone formation and resorption are within normal limits. These findings, at least the consistent set of data obtained in the C57CB1-/- line, suggest an important role for CB1 signalling in the regulation of bone remodelling and bone mass. Because sympathetic CB1 signalling inhibits norepinephrine (NE) release in peripheral tissues, part of the endocannabinoid activity in bone may be attributed to the regulation of NE release from sympathetic nerve fibers. Several phenotypic discrepancies have been reported between C57CB1-/- and CD1CB1-/- mice, which could result from genetic differences between the background strains. Unraveling these differences can provide useful information on the physiologic functional milieu of CB1 in bone.


Key words: Adrenergic, Cannabinoid, Knockout


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