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. 2010 Sep;8(3):243-53.
doi: 10.2174/157015910792246173.

Cannabinoid Receptors as Target for Treatment of Osteoporosis: A Tale of Two Therapies

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Free PMC article

Cannabinoid Receptors as Target for Treatment of Osteoporosis: A Tale of Two Therapies

Aymen I Idris. Curr Neuropharmacol. .
Free PMC article

Abstract

The central nervous system plays an important role in regulating bone metabolism in health and in disease with a number of neurotransmitters been reported to influence bone cell activity through a central relay. In keeping with this, recent studies demonstrated that endocannabinoids and their receptors are involved in the pathogenesis of osteoporosis. The endocannabinoids anandamide and 2-arachidonylglycerol are found in the skeleton and numerous studies also showed that bone cells express the cannabinoid receptors CB1 and CB2 and the orphan receptor GPR55. Pharmacological and genetic inactivation of CB1, CB2 and GPR55 in adult mice suppress bone resorption, increase bone mass and protect against bone loss, suggesting that inverse agonists/antagonists of these receptors may serve as anti-resorptive agents. In the ageing skeleton however CB1 and CB2 receptors have a protective effect against age-dependent bone loss in both male and female mice. CB1 receptor deficiency in aged mice results in accelerated age-dependent osteoporosis due to marked increase in bone resorption and significant reduction in bone formation coupled to enhanced adipocyte accumulation in the bone marrow compartment. Similar acceleration of bone loss was also reported in CB2 deficient mice of similar age but found to be associated with enhanced bone turnover. This review summarises in vitro and in vivo findings relating to the influence of cannabinoid ligands on bone metabolism and argues in favour of the exploitation of cannabinoid receptors as targets for both anabolic and anti-resorptive therapy for treatment of complex multifaceted bone diseases such as osteoporosis.

Keywords: CB1; CB2; Cannabinoid; GPR55.; Rimonabant©; anabolic; anti-resorptive; bone; osteoporosis.

Figures

Fig. (1)
Fig. (1)
The bone remodelling cycle. Upon stimulus, embedded osteocytes within the bone matrix attract osteoclasts and their precursors to the remodelling site. Mature osteoclasts first attach to bone surface and then resorb the bone matrix (bone resorption). Following resorption and osteoclast apoptosis, there is a reversal phase during which osteoblast recruitment and proliferation occurs. Fully differentiated osteoblast deposit osteoid on the resorption site thereby initiating bone formation. Bone formation is followed by a phase during which freshly laid osteoid becomes mineralised and covered by bone lining cells.
Fig. (2)
Fig. (2)
Schematic illustration of the current model of local and systemic regulation of bone cell differentiation and function by cannabinoid ligands. Leptin regulates bone mass through a neuronal hypothalamic relay involving β-adrenergic neurones and endocannabinoid system within the sympathetic nervous system (SNS). Noradrenaline is known to increase bone loss by stimulating osteoclast formation and resorption. Cannabinoid receptors are likely to influence the hypothalamic action of leptin on bone formation by a central relay. Moreover, mature osteoblasts express CB1 and CB2 receptors and secrete AEA and 2-AG that in turn enhance RANKL induced osteoclast formation, thereby influencing osteoblast-osteoclast coupling. Cannabinoid ligands (CBL) are also involved in the regulation of osteoclast survival, polarisation and activity by acting on CB1 and CB2 receptors expressed on mature osteoclasts. CBL are capable of regulating bone formation by either directly acting on CB1 and CB2 receptors on osteoblasts or indirectly by inhibiting the production of the catecholamine noradrenaline, an inhibitor of osteoblast differentiation. Acting on CB1 receptors expressed on BM stromal cells, cannabinoid receptor agonists stimulate osteoblast differentiation and inhibit adipocyte accumulation in the bone marrow. TRPV1 and GPR55 expressed by osteoblasts and osteoclasts are likely to be responsible for some of the skeletal action of AEA and other cannabinoid ligands. Abbreviation: SNS - sympathetic nervous system; CB – cannabinoid; RANKL - receptor activator of NFκ B ligand; VD3 – vitamin D3, M-CSF - macrophage colony stimulating factor; cfms - M-CSF receptor; NA – noreadrenaline; AEA – anandamide; CBD – cannabidiol. Question mark (?) denotes unknown factors.
Fig. (3)
Fig. (3)
Hypothetical model for prevention and treatment of postmenopausal osteoporosis using cannabinoid ligands. Cannabinoid receptors play a role in regulating osteoclast and osteoblast differentiation and activity in the ageing skeleton. Osteoblast and osteoclast activity are balanced during skeletal growth and early adulthood. Following oestrogen deficiency after menopause, acute bone loss occurs due to a significant rise in osteoclast number. During this phase, cannabinoid receptor inverse agonists/antagonists may prevent excessive bone loss by reducing osteoclast number and bone resorption. Activation of cannabinoid receptors using cannabinoid agonist may restore bone loss incurred during the prolonged phase of bone loss by promoting osteoblast differentiation and bone formation.

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