Regulation of bone mass, bone loss and osteoclast activity by cannabinoid receptors.
Accelerated osteoclastic bone resorption has a central role in the pathogenesis of osteoporosis and other bone diseases. Identifying the molecular pathways that regulate osteoclast activity provides a key to understanding the causes of these diseases and to the development of new treatments. Here we show that mice with inactivation of cannabinoid type 1 (CB1) receptors have increased bone mass and are protected from ovariectomy-induced bone loss. Pharmacological antagonists of CB1 and CB2 receptors prevented ovariectomy-induced bone loss in vivo and caused osteoclast inhibition in vitro by promoting osteoclast apoptosis and inhibiting production of several osteoclast survival factors. These studies show that the CB1 receptor has a role in the regulation of bone mass and ovariectomy-induced bone loss and that CB1- and CB2-selective cannabinoid receptor antagonists are a new class of osteoclast inhibitors that may be of value in the treatment of osteoporosis and other bone diseases.
Idris
Aymen I
AI
Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK.
van 't Hof
Robert J
RJ
Greig
Iain R
IR
Ridge
Susan A
SA
Baker
David
D
Ross
Ruth A
RA
Ralston
Stuart H
SH
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015519:Bone Density / Q000235:genetics; D001862:Bone Resorption; D001842:Bone and Bones / Q000033:anatomy & histology / Q000187:drug effects; D001892:Camphanes / Q000494:pharmacology; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D007211:Indoles / Q000494:pharmacology; D008024:Ligands; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism*; D010052:Ovariectomy; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D053245:RANK Ligand; D011817:Rabbits; D053246:Receptor Activator of Nuclear Factor-kappa B; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors / Q000378:metabolism*
D001892:Camphanes; D002352:Carrier Proteins; D007211:Indoles; D008024:Ligands; D008562:Membrane Glycoproteins; D010880:Piperidines; D011720:Pyrazoles; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C110630:SR 144528; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; C103505:AM 251; C094023:iodopravadoline