Bone is a dynamic living organ that differentiates vertebrates from other animals. Calcification makes the tissue dense, stiff, strong and careful control of the material and geometrical properties of bone attempts to match their properties to the prevailing mechanical environment. Bone homeostasis involves an array of factors, only a few of which are known. The cells that produce bone, osteoblasts, share a common origin with adipocytes in mesenchymal stem cells (MSC) and there is mounting evidence of dysregulation of MSC differentiation in bone disorders such as osteoarthritis and osteoporosis. The cannabinoid system has recently been shown to be involved in bone homeostasis and has been proposed as a potential therapeutic target for treatment of bone diseases. However studies published to date look almost exclusively at its effect on trabecular bone. A full understanding of any regulatory factor can come only by considering both cortical and trabecular bone. This thesis describes experiments to characterize the mechanical, material and geometrical properties of cortical and trabecular bone from mice in which cannabinoid, CB1, CB2, or putative cannabinoid, GPR55, receptors have been deleted. Further studies started to explore the biological basis underlying the role of GPR55 and one of its antagonists, cannabidiol (CBD). The hypothesis was that endogenous cannabinoids can regulate bone properties and the aim Abstract ii was to resolve discrepancies found in previous studies and begin to explore the effect of cannabidiol acting through the GPR55 receptor on MSC differentiation. CB1 -/- mice had inferior mechanical properties to wild type mice due to reduced geometrical properties while the material properties remained unchanged. No change was found in trabecular bone volume in males but female CB1 -/- mice showed a high bone mass phenotype. CB2 -/- mice had mechanically superior bones to wild type animals due to larger geometrical properties. These superior characteristics were also seen in trabecular bone, where the female KOs had a high bone mass phenotype. The effect of knocking out GPR55 showed an increase in the amount of both cortical and trabecular bone. The knockout mice were fatter and were protected against age related bone loss. In addition, CBD enhanced adipogenesis in both humans and mice, while no effects were seen on osteogenesis. Enhanced adipogenesis was also found in GPR55-/- cell cultures. These results suggest that blocking GPR55 with small molecules such as CBD may be beneficial in bone diseases such as osteoporosis but not osteoarthritis.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:589495 |
| Date | January 2013 |
| Creators | Khalid, Aysha Binty |
| Publisher | University of Aberdeen |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=202765 |
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