Cannabinoids and the skeleton: From marijuana to reversal of bone loss THC Activates CB1 and CB2

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Annals of Medicine. 2009; 41: 560􏰃567 REVIEW ARTICLE Cannabinoids and the skeleton: From marijuana to reversal of bone loss ITAI BAB1, ANDREAS ZIMMER2 & EITAN MELAMED1 1Bone Laboratory, the Hebrew University of Jerusalem, Jerusalem, Israel, and 2Institute of Molecular Psychiatry, University of Bonn, Bonn, Germany Abstract The active component of marijuana, D9-tetrahydrocannabinol, activates the CB1 and CB2 cannabinoid receptors, thus mimicking the action of endogenous cannabinoids. CB1 is predominantly neuronal and mediates the cannabinoid psychotropic effects. CB2 is predominantly expressed in peripheral tissues, mainly in pathological conditions. So far the main endocannabinoids, anandamide and 2-arachidonoylglycerol, have been found in bone at ‘brain’ levels. The CB1 receptor is present mainly in skeletal sympathetic nerve terminals, thus regulating the adrenergic tonic restrain of bone formation. CB2 is expressed in osteoblasts and osteoclasts, stimulates bone formation, and inhibits bone resorption. Because low bone mass is the only spontaneous phenotype so far reported in CB2 mutant mice, it appears that the main physiologic involvement of CB2 is associated with maintaining bone remodeling at balance, thus protecting the skeleton against age-related bone loss. Indeed, in humans, polymorphisms in CNR2, the gene encoding CB2, are strongly associated with postmenopausal osteoporosis. Preclinical studies have shown that a synthetic CB2-specific agonist rescues ovariectomy-induced bone loss. Taken together, the reports on cannabinoid receptors in mice and humans pave the way for the development of 1) diagnostic measures to identify osteoporosis-susceptible polymorphisms in CNR2, and 2) cannabinoid drugs to combat osteoporosis. Key words: Bone, cannabinoid, endocannabinoid, marijuana, osteoporosis Introduction The marijuana plant Cannabis Sativa has been cultivated for thousands of years for medical and recreational use in the form of marijuana or hashish. Its psychoactive effects have made it the most common drug of abuse. However, it affects not only the brain but virtually every organ system in the body. We now know that the active component of marijuana, D9-tetrahydrocannabinol (THC), acts on two distinct receptors that are distributed through- out the body, only one of which mediates the psychotropic effects. These receptors respond to endogenous ligands, termed endocannabinoids, with THC just mimicking the activity of these physiological activators. The endocannabinoids are produced and degraded by specific enzymes. Together, the receptors, ligands, and enzymes com- prise the endocannabinoid system. The on-going discovery of this system during the last two decades and its relevance for many organ systems has fueled extensive research and tremendous interest from pharmaceutical companies for potential therapeutic applications. Progress in this field has exploded in the last decade. There is a huge literature, growing by the day, investigating the endocannabinoid system in neural and non-neural tissues. Numerous excel- lent reviews have appeared in the last several years that treat the history, biochemistry, pharmacology, and therapeutic potential of this system (1􏰃8). In ancient times, Cannabis was used therapeuti- cally to relieve pain, reduce inflammation, and as a sedative. It was also used extensively to treat migraine headaches and ulcers. It is now well established that THC produces numerous beneficial effects, including analgesia, appetite stimulation, nausea reduction, and reduction of intraocular pressure. THC also affects fertility, short-term memory, tumor growth, and motor co-ordination (9,10). The therapeutic use of THC has been hampered by psychotropic effects that have pre- vented general acceptance by the Federal Drug Administration (FDA). MarinolT M , a synthetic Correspondence: Professor Itai Bab, Bone Laboratory, The Hebrew University of Jerusalem, PO Box 12272, Jerusalem 91120, Israel. Fax: 􏰂972-2-675-7623. E-mail: babi@cc.huji.ac.il ISSN 0785-3890 print/ISSN 1365-2060 online # 2009 Informa UK Ltd. DOI: 10.1080/07853890903121025 Ann Med Downloaded from informahealthcare.com by Stanford University on 01/13/11 For personal use only.

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