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Title: An investigation into the effects of endocannabinoids and the COX-2 metabolite of 2-Arachidonyl glycerol on bone cells
Author: Ford, Lorna
ISNI:       0000 0004 2677 6747
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2009
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The effects of endocannabinoids on human, mouse and rabbit bone cells were investigated.  At high concentrations anandamide and 2-arachidonyl glycerol (2-AG) inhibited human osteoclast formation with no effects at lower concentrations. The inhibition was not attenuated by antagonists for the CB1, CB2 or TRPV1 receptors, indicating a non-receptor mediated effect.  Conversely, anandamide and 2-AG increased mouse osteoclast formation.  The effect of anandamide was enhanced in cells from fatty acid amide hydrolase (FAAH)-null mice and abolished in cells from CB1/2 knockout mice.  The effect of 2-AG was not eliminated in CB1/2 knockout cells, indicating a non-CB1/CB2 action.  The CB1 antagonist, AM251, and the CB2 antagonist, AM630, both inhibited mouse osteoclast formation.  These effects were not rescued in the CB1/2-knockout mouse cells.  Both anandamide and 2-AG stimulated actin ring formation and osteoclast activity in human and rabbit osteoclast.  This was prevented in the presence of AM630 but not AM251, indicating a CB2-mediated response.  The endocannabinoids and the cannabinoid receptor antagonists do not have a regulatory action on osteoblast activity. The effects of the novel cyclooxygenase-2 (COX-2) metabolite of 2-AG, prostaglandin E2-glycerol ester (PGE2-G), on human osteoclasts were examined.  Treatment with PGE2-G inhibited formation and ERK phosphorylation of human osteoclasts.  These effects were attenuated by a selective EP4 antagonist and mimicked by PGE2 alone, indicating that PGF2-G is rapidly metabolised into PGE2 in human osteoclast cultures.  However, PGE2-G treatment elevated intracellular calcium levels in human osteoclasts, through a phospholipase C (PLC)- and IP3- dependent mechanism, indicative of a G-protein coupled receptor effect.  This was not mimicked by PGE2, or prevented by the EP4 antagonist, but blocked by a putative PGE2-G receptor antagonist, PDA-94 indicating that PDA-94 may be a PGE2-G receptor antagonist.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Bones ; Osteoclasts ; Endocannabinoids