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...

Cnr2 is one of two cannabinoid receptors known to regulate bone metabolism. Here, we compared the whole bone properties of femora and tibiae from three-month-old Cnr2−/− mice with wild-type controls using a C57BL/6 background. Bending stiffness was measured by three-point bending. The elastic modulus, density and mineral content were measured using ultrasound, Archimedes’ principle and ashing. Micro-CT was used to measure the second moment of area, inner and outer perimeters of the cortical shaft and trabecular parameters. Deleting Cnr2 increased the bending stiffness by increasing the second moment of area. Bone from affected male mice had a greater modulus than controls, although no difference...

The endogenous cannabinoids bind to and activate two G proteincoupled receptors, the predominantly central cannabinoid receptor type 1 (CB1) and peripheral cannabinoid receptor type 2 (CB2). Whereas CB1 mediates the cannabinoid psychotropic, analgesic, and orectic effects, CB2 has been implicated recently in the regulation of liver fibrosis and atherosclerosis. Here we show that CB2-deficient mice have a markedly accelerated age-related trabecular bone loss and cortical expansion, although cortical thickness remains unaltered. These changes are reminiscent of human osteoporosis and may result from differential regulation of trabecular and cortical bone remodeling. The CB2 / phenotype is also characterized by increased activity of trabecular osteoblasts (bone-forming...

Disc degeneration is a multifactorial process that involves hypoxia, inflammation, neoinnervation, accelerated catabolism, and reduction in water and glycosaminoglycan content. Cannabidiol is the main non-psychotropic component of the Cannabis sativa with protective and anti-inflammatory properties. However, possible therapeutic effects of cannabidiol on intervertebral disc degeneration have not been investigated yet. The present study investigated the effects of cannabidiol intradiscal injection in the coccygeal intervertebral disc degeneration induced by the needle puncture model using magnetic resonance imaging (MRI) and histological analyses. Disc injury was induced in the tail of male Wistar rats via a single needle puncture. The discs selected for injury were punctured percutaneously...

The endocannabinoid system plays a key role in regulating a variety of physiological processes such as appetite control and energy balance, pain perception, and immune responses. Recent studies have implicated the endocannabinoid system in the regulation of bone cell activity and bone remodeling.These studies showed that endogenous cannabinoid ligands, cannabinoid receptors, and the enzymes responsible for ligand synthesis and breakdown all play important roles in bone mass and in the regulation of bone disease. These findings suggest that the endocannabinoid pathway could be of value as a therapeutic target for the prevention and treatment of bone diseases. Here, we review the role of the...

We have recently reported that in bone the cannabinoid CB1 receptor is present in sympathetic terminals. Here we show that traumatic brain injury (TBI), which in humans enhances peripheral osteogenesis and fracture healing, acutely stimulates bone formation in a distant skeletal site. At this site we demonstrate i) a high level of the main endocannabinoid, 2-arachidonoylglycerol (2-AG), and expression of diacylglycerol lipases, enzymes essential for 2-AG synthesis; ii) that the TBIinduced increase in bone formation is preceded by elevation of the 2-AG and a decrease in norepinephrine (NE) levels. The TBI stimulation of bone formation was absent in CB1-null mice. In wild-type animals it...

Cannabinoid receptors play an important role in regulating bone mass and bone turnover. Studies in our laboratories have shown that young mice lacking type 1 cannabinoid receptor (CNR1-/-) had increased bone mass and were resistant to ovariectomy-induced bone loss. Other workers have reported that type 2 cannabinoid receptor knockout mice (CNR2-/-) develop age-related osteoporosis. The aim of this PhD thesis was to further investigate the role of CNR2 in bone metabolism in vitro and in vivo, using genetic and pharmacological approaches.