Given the recent finding that the cannabinoid receptors CB<sub>1</sub> and CB<sub>2</sub> affect bone metabolism, we examined the role of GPR55 in bone biology. GPR55 was expressed in human and mouse osteoclasts and osteoblasts; expression was higher in human osteoclasts than in macrophage progenitors. Although the GPR55 agonists O-1602 and LPI inhibited mouse osteoclast formation <i>in vitro</i>, these ligands stimulated mouse and human osteoclast polarisation and resorption <i>in vitro</i> and caused activation of Rho and ERK1/2. These stimulatory effects on osteoclast function were attenuated in osteoclasts generated from GPR55<sup>-/-</sup> macrophages and by the GPR55 antagonist cannabidiol (CBD). Furthermore, treatment of mice with this non-psychoactive constituent of cannabis significantly reduced bone resorption <i>in vivo</i>. Consistent with the ability of GPR55 to suppress osteoclast formation but stimulate osteoclast function, histomorphometric and microcomputed tomographic analysis of the long bones from male GPR55<sup>-/-</sup> mice revealed increased numbers of morphologically-inactive osteoblasts, but a significant increase in the volume and thickness of trabecular bone and the presence of unresorbed cartilage. These data reveal a hitherto unrecognised role of GPR55 in bone physiology by regulating osteoclast number and function. In addition, this study also brings to light a newly identified effect of both the endogenous ligand, LPI , on osteoclasts and of the cannabis constituent, CBD, on osteoclasts and bone turnover <i>in vivo</i>. These results suggest that blocking GPR55 with small molecules similar to CBD may be beneficial in bone diseases associated with increased osteoclast activity such as osteoporosis.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:522232 |
| Date | January 2009 |
| Creators | Whyte, Lauren Sarah |
| 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=103940 |
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