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From Marijuana to Reversal of Bone Loss Annals of Medicine. 2009; 41: 560Á567 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 For personal use only. Introduction pharmaceutical companies for potential therapeutic applications. Progress in this field has exploded in The marijuana plant Cannabis Sativa has been the last decade. There is a huge literature, growing cultivated for thousands of years for medical and recreational use in the form of marijuana or hashish. by the day, investigating the endocannabinoid system Its psychoactive effects have made it the most in neural and non-neural tissues. Numerous excel- common drug of abuse. However, it affects not lent reviews have appeared in the last several years only the brain but virtually every organ system in that treat the history, biochemistry, pharmacology, Ann Med Downloaded from informahealthcare.com by Stanford University on 01/13/11 the body. We now know that the active component of and therapeutic potential of this system (1Á8). marijuana, D9-tetrahydrocannabinol (THC), acts on In ancient times, Cannabis was used therapeuti- two distinct receptors that are distributed through- cally to relieve pain, reduce inflammation, and as a out the body, only one of which mediates the sedative. It was also used extensively to treat psychotropic effects. These receptors respond to migraine headaches and ulcers. It is now well endogenous ligands, termed endocannabinoids, established that THC produces numerous beneficial with THC just mimicking the activity of these effects, including analgesia, appetite stimulation, physiological activators. The endocannabinoids are nausea reduction, and reduction of intraocular produced and degraded by specific enzymes. pressure. THC also affects fertility, short-term Together, the receptors, ligands, and enzymes com- memory, tumor growth, and motor co-ordination prise the endocannabinoid system. The on-going (9,10). The therapeutic use of THC has been discovery of this system during the last two decades hampered by psychotropic effects that have pre- and its relevance for many organ systems has fueled vented general acceptance by the Federal Drug extensive research and tremendous interest from Administration (FDA). MarinolTM, 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: [email protected] ISSN 0785-3890 print/ISSN 1365-2060 online # 2009 Informa UK Ltd. DOI: 10.1080/07853890903121025 Cannabinoids and bone 561 Key messages Abbreviations . Several key components of the endocanna- 2-AG 2-arachidonoylglycerol binoid system have been identified in bone. b2AR b2-adrenergic receptor . The main physiologic involvement of CB2 BMP bone morphogenetic protein (type 2 cannabinoid receptor) is associated DAGL diacylglycerol lipase FAAH fatty acid amide hydrolase with maintaining bone remodeling at IL-6 interleukin 6 balance. MAPK mitogen-activated protein kinase . CB2 agonists are possible candidates for a M-CSF macrophage colony-stimulating factor combined antiresorptive and anabolic ther- NAPE- N-acyl phosphatidyl ethanolamine apy for osteoporosis. PLD phospholipase D OGP osteogenic growth peptide OPG osteoprotegerin THC in sesame oil, is the only FDA-approved OVX ovariectomy cannabinoid agonist for use in the US. It is PTH parathyroid hormone prescribed as an appetite stimulant in AIDS, gastric RANKL receptor activator of NFkB ligand SNP single nucleotide polymorphism by-pass, and chemotherapy patients and also as an 9 TM THC D -tetrahydrocannabinol antiemetic for chemotherapy. Sativex was ap- TRPV1 transient receptor potential vanilloid type 1 proved by Health Canada in 2005 to relieve pain receptor and spasticity in multiple sclerosis. It is a sublingual spray made by blending two of the main active ingredients of cannabis, THC and cannabidiol of resorption and formation of the mineralized (CBD), and used for the relief of neuropathic pain. matrix, referred to as bone remodeling. The remo- It has been recently (December 2008) approved by deling process occurs concomitantly in multiple foci the FDA for stage III clinical trials in the US. An that encompass approximately 5% of trabecular, antagonist of the type I cannabinoid receptor (CB1), endosteal, and osteonal surfaces (15). The remodel- TM marketed as Acomplia by Sanofi Aventis, was ing cycle in individual foci consists of a relatively approved for use as an antiobesity drug in the rapid (i.e. a few weeks in humans) resorption of European Union in 2006. It also blocks the pre-existing mineralized matrix by a specific hema- For personal use only. weight-gain associated with nicotine withdrawal, topoietic, monocyte-derived cell type, the osteoclast reduces visceral fat content, and lowers LDL levels. (16). It is then followed by a slower (i.e. a However, its marketing in Europe as well as stage III few months) stage of bone formation by another TM clinical trials of Acomplia in the US have been bone-specific, fibroblast-like cell type, the osteoblast recently halted due to a 2-fold increase in psychiatric (17). Different foci present different phases of the (depression, anxiety, irritability) and gastrointestinal remodeling cycle. Healthy adults retain an overall (nausea) side-effects (11). balance between bone resorption and formation. Recently, there has been a rapidly growing The significance of balanced bone remodeling is interest in the role of cannabinoids in the regulation Ann Med Downloaded from informahealthcare.com by Stanford University on 01/13/11 demonstrated by osteoporosis, the most common of skeletal remodeling and bone mass, addressed in metabolic bone disease in developed societies, which basic, translational, and clinical research. A recent results from a net increase in bone resorption and citation search revealed as many as 80 publications bone loss, weakening of the skeleton, and increased addressing the skeletal cannabinoid system since the fracture risk. first publications in 2005 (12,13). This review The co-ordinated occurrence of multiple remo- focuses on the skeletal cannabinoid system as a deling sites is suggestive of a complex hierarchical therapeutic target for patients with osteoporosis and regulation consisting of local, autocrine/paracrine, other skeletal deficits. and systemic endocrine regulatory systems (18). Indeed, numerous studies have demonstrated para- crine control of osteoclast formation and activity by Skeletal remodeling factors such as receptor activator of NFkB ligand Bone structure displays sequential stages throughout (RANKL), osteoprotegerin (OPG), macrophage life, comprising 1) a rapid skeletal growth phase colony-stimulating factor (M-CSF) and interleukin accompanied by accrual of peak bone mass; 2) a 6 (IL-6), which are derived from neighboring steady state phase whereby bone mass remains stromal cells, including osteoblasts and their constant; and 3) age-related bone loss (14). These precursors (19Á24). Locally, osteoblasts are regu- changes are the consequence of a continuous process lated mainly by bone morphogenetic proteins 562 I. Bab et al. (BMPs) and Wnts (25,26). Systemically, it is well anandamide concentrations have been attributed to established that depletion of gonadal hormones in low substrate (arachidonic acid esterified at the females and males favors bone loss (27Á29). In 1-position) levels for this pathway and/or the short addition, parathyroid hormone (PTH) (30,31), anandamide half-life in vivo (t1/2 B5 min) (52,53). calcitonin (32), insulin-like growth factor I (IGF-I) Anandamide is biosynthesized through N-acyl phos- (33), osteogenic growth peptide (OGP) (34), and phatidyl ethanolamine phospholipase D (NAPE- duodenum-derived serotonin (35) are involved in PLD)-dependent and -independent pathways (54). the control of bone formation.
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