Regulation of skeletal remodeling by the endocannabinoid system.

Since the discovery of the endocannabinoid system, its presence and involvement have been reported in a handful of biological systems. Recently, the skeleton has been identified as a major endocannabinoid target through both the neuronal CB1 and predominantly peripheral CB2 cannabinoid receptors. CB1 is present in sympathetic nerve terminals in bone, whereas CB2 is expressed in osteoblasts and osteoclasts, the respective bone-forming and -resorbing cells. Furthermore, the skeleton appears as the main system physiologically regulated by CB2. CB2-deficient mice show a markedly accelerated age-related bone loss and the CB2 locus in women is associated with low bone density and osteoporotic fractures. Since activation of CB2 attenuates experimentally induced bone loss by inhibiting bone resorption and stimulating bone formation, and because synthetic cannabinoids are stable and orally available, a therapy based on synthetic CB2 agonists is a promising novel target for antiosteoporotic drug development.