Cannabinoid ligands regulate bone mass, but skeletal effects of cannabis (marijuana and hashish) have not been reported. Bone fractures are highly prevalent, involving prolonged immobilization and discomfort. Here we report that the major non-psychoactive cannabis constituent, cannabidiol (CBD), enhances the biomechanical properties of healing rat mid-femoral fractures. The maximal load and work-to-failure, but not the stiffness, of femurs from rats given a mixture of CBD and D 9-tetrahydrocannabinol (THC) for 8 weeks were markedly increased by CBD. This effect is not shared by THC (the psychoactive component of cannabis), but THC potentiates the CBD stimulated work-to-failure at 6 weeks postfracture followed by attenuation of the CBD effect at 8 weeks. Using micro-computed tomography (mCT), the fracture callus size was transiently reduced by either CBD or THC 4 weeks after fracture but reached control level after 6 and 8 weeks. The callus material density was unaffected by CBD and/or THC. By contrast, CBD stimulated mRNA expression of Plod1 in primary osteoblast cultures, encoding an enzyme that catalyzes lysine hydroxylation, which is in turn involved in collagen crosslinking and stabilization. Using Fourier transform infrared (FTIR) spectroscopy we confirmed the increase in collagen crosslink ratio by CBD, which is likely to contribute to the improved biomechanical properties of the fracture callus. Taken together, these data show that CBD leads to improvement in fracture healing and demonstrate the critical mechanical role of collagen crosslinking enzymes.
Most in vivo studies addressing the skeletal responses of mice to mechanical loading have targeted cortical bone. To investigate trabecular bone responses also we have developed a caudal vertebral axial compression device (CVAD) that transmits mechanical loads to compress the fifth caudal vertebra via stainless steel pins inserted into the forth and sixth caudal vertebral bodies. Here, we used the CVAD in C57BL/6 (B6) and C3H/Hej (C3H) female mice (15 weeks of age) to investigate whether the effect of regular bouts of mechanical stimulation on bone modeling and bone mass was dependent on dose and genotype. A combined micro-computed tomographic and dynamic histomorphometric analysis was carried out at the end of a 4-week loading regimen (3,000 cycles, 10 Hz, 3 x week) for load amplitudes of 0N, 2N, 4N and 8N. Significant increases in trabecular bone mass of 9 and 21% for loads of 4N and 8N, respectively, were observed in B6 mice. A significant increase of 10% in trabecular bone mass occurred for a load of 8N in the C3H strain. For other loads, no significant increases were detected. Both mouse strains exhibited substantial increases in trabecular bone formation rates for all loads, B6: 111% (2N), 86% (4N), 164% (8N), C3H: 41% (2N), 38% (4N), 141% (8N). Significant decreases in osteoclast number of 146 and 93% for a load of 8N were detected in B6 and C3H mice, respectively. These findings demonstrate that the effect of loading on the structural and functional parameters of bone is dose and genotype dependent. The caudal vertebral loading model established here is proposed for further studies addressing the molecular processes involved in the skeletal responses to mechanical stimuli. Here we used the CVAD in C57BL/6 and C3H/Hej mice to investigate whether the effect of regular bouts of mechanical stimulation on bone remodeling and bone mass were dependent on dose and genotype. A combined micro-computed tomographic and dynamic histomorphometric analysis carried out at the end of a 4-week loading regimen for load amplitudes of 0N, 2N, 4N and 8N revealed that an amplitude of 8N stimulated significant increases in trabecular and cortical bone mass mainly in the C57BL/6 strain. Both biological strains exhibited substantial increases in bone formation rates and decreases in osteoblast number. These findings demonstrate that the effect of loading on the structural and functional parameters of bone is dose-and genotype dependent. The caudal vertebral loading model established here is proposed for further studies addressing the molecular processes involved in the skeletal responses to mechanical stimuli.
The endocannabinoid (EC) system regulates bone mass. Because cannabis use during pregnancy results in stature shorter than normal, we examined the role of the EC system in skeletal elongation. We show that CB1 and CB2 cannabinoid receptors are expressed specifically in hypertrophic chondrocytes of the epiphyseal growth cartilage (EGC), which drives vertebrate growth. These cells also express diacylglycerol lipases, critical biosynthetic enzymes of the main EC, and 2-arachidonoylglycerol (2-AG), which is present at significant levels in the EGC. Femora of CB1- and/or CB2-deficient mice at the end of the rapid growth phase are longer compared to wild-type (WT) animals. We find that Δ(9) -tetrahydrocannabinol (THC) slows skeletal elongation of female WT and CB2-, but not CB1-, deficient mice, which is reflected in femoral and lumbar vertebral body length. This in turn results in lower body weight, but unaltered fat content. THC inhibits EGC chondrocyte hypertrophy in ex vivo cultures and reduces the hypertrophic cell zone thickness of CB1-, but not CB2-, deficient mice. These results demonstrate a local growth-restraining EC system in the EGC. The relevance of the present findings to humans remains to be studied.
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