title: Cannabidiol, a Major Non-Psychotropic Cannabis Constituent Enhances Fracture Healing and Stimulates Lysyl Hydroxylase Activity in Osteoblasts.
abstract: 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 Δ(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 (μCT), 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.
authors: Bone Laboratory, Hebrew University of Jerusalem, Jerusalem, Israel.
authors: Natalya M
authors: NM
authors: Kogan
authors: Bone Laboratory, Hebrew University of Jerusalem, Jerusalem, Israel.
authors: Eitan
authors: E
authors: Melamed
authors: Bone Laboratory, Hebrew University of Jerusalem, Jerusalem, Israel.
authors: Elad
authors: E
authors: Wasserman
authors: Bone Laboratory, Hebrew University of Jerusalem, Jerusalem, Israel.|Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors: Bitya
authors: B
authors: Raphael
authors: Institute for Drug Research, Hebrew University of Jerusalem, Jerusalem, Israel.
authors: Aviva
authors: A
authors: Breuer
authors: Institute for Biomechanics, ETH Zürich, Zürich, Switzerland.
authors: Kathryn S
authors: KS
authors: Stok
authors: Institute for Biomechanics, ETH Zürich, Zürich, Switzerland.
authors: Rachel
authors: R
authors: Sondergaard
authors: Institute for Biomechanics, ETH Zürich, Zürich, Switzerland.
authors: Ana V Villarreal
authors: AV
authors: Escudero
authors: Bone Laboratory, Hebrew University of Jerusalem, Jerusalem, Israel.
authors: Saja
authors: S
authors: Baraghithy
authors: Bone Laboratory, Hebrew University of Jerusalem, Jerusalem, Israel.
authors: Malka
authors: M
authors: Attar-Namdar
authors: Department of Oral Medicine, Hadassah-Hebrew University Faculty of Dental Medicine, Jerusalem, Israel.
authors: Silvina
authors: S
authors: Friedlander-Barenboim
authors: Department of Biomedical Engineering, Lund University, Lund, Sweden.|Department of Orthopedics, Lund University, Lund, Sweden.
authors: Neashan
authors: N
authors: Mathavan
authors: Department of Biomedical Engineering, Lund University, Lund, Sweden.|Department of Orthopedics, Lund University, Lund, Sweden.
authors: Hanna
authors: H
authors: Isaksson
authors: Institute for Drug Research, Hebrew University of Jerusalem, Jerusalem, Israel.
authors: Raphael
authors: R
authors: Mechoulam
authors: Institute for Biomechanics, ETH Zürich, Zürich, Switzerland.
authors: Ralph
authors: R
authors: Müller
authors: Bone Laboratory, Hebrew University of Jerusalem, Jerusalem, Israel.
authors: Alon
authors: A
authors: Bajayo
authors: Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors: Yankel
authors: Y
authors: Gabet
authors: Bone Laboratory, Hebrew University of Jerusalem, Jerusalem, Israel.
authors: Itai
authors: I
authors: Bab
mesh_terms: D000818:Animals; D002185:Cannabidiol / Q000737:chemistry / Q000494:pharmacology*; D002188:Cannabis / Q000737:chemistry*; D005264:Femoral Fractures / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000201:enzymology; D017102:Fracture Healing / Q000187:drug effects*; D051379:Mice; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / Q000378:metabolism*; D051381:Rats; D055114:X-Ray Microtomography
chemical_list: D002185:Cannabidiol; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase
keywords: CANNABIDIOL; COLLAGEN CROSSLINKING; FRACTURE HEALING; FTIR; LYSYL HYDROXYLASE; μCT