Endocannabinoids and the regulation of bone metabolism

In mammals, including humans, bone metabolism is manifested as an ongoing modelling/remodelling process whereby the bone mineralised matrix is being continuously renewed. Recently, the main components of the endocannabinoid system have been reported in the skeleton. Osteoblasts, the bone forming cells, and other cells of the osteoblastic lineage, as well as osteoclasts, the bone resorbing cells, and their precursors, synthesise the endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG). CB₁ cannabinoid receptors are present in sympathetic nerve terminals in close proximity to osteoblasts. Activation of these CB₁ receptors by elevated bone 2-AG levels communicates brain-to-bone signals as exemplified by traumatic brain injury-induced stimulation of bone formation. In this process, the retrograde CB₁ signalling inhibits noradernaline release and alleviates the tonic sympathetic restrain of bone formation. CB₂ receptors are expressed by osteoblasts and osteoclasts. Their activation stimulates bone formation and suppresses bone resorption. CB₂-deficient mice display a markedly accelerated age-related bone loss. Ovariectomy-induced bone loss can be both prevented and rescued by a CB₂ specific agonist. Hence, synthetic CB₂ ligands, which are stable and orally available, provide a basis for developing novel anti-osteoporotic therapies, free of psychotropic effects. The CNR2 gene (encoding CB₂) in women is associated with low bone mineral density, offering an assay for identifying females at risk of developing osteoporosis.