Accelerated osteoclastic bone resorption has a central role in the pathogenesis of osteoporosis and other bone diseases. Identifying the molecular pathways that regulate osteoclast activity provides a key to understanding the causes of these diseases and to the development of new treatments. Here we show that mice with inactivation of cannabinoid type 1 (CB1) receptors have increased bone mass and are protected from ovariectomy-induced bone loss. Pharmacological antagonists of CB1 and CB2 receptors prevented ovariectomy-induced bone loss in vivo and caused osteoclast inhibition in vitro by promoting osteoclast apoptosis and inhibiting production of several osteoclast survival factors. These studies show that the CB1 receptor has a role in the regulation of bone mass and ovariectomy-induced bone loss and that CB1- and CB2-selective cannabinoid receptor antagonists are a new class of osteoclast inhibitors that may be of value in the treatment of osteoporosis and other bone diseases.
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This study was supported by a project grant from the arthritis research campaign to S.H.R., R.A.R. and R.V.H.; a “Proof of Concept” grant to S.H.R., I.R.G. and R.V.H. from Scottish Enterprise; and by a US National Institutes of Health grant to R.A.R. R.V.H. is supported by a project grant from the arthritis research campaign and D.B. is a Multiple Sclerosis Society senior fellow.
The authors hold patents on the use of cannabinoid receptor ligands as treatments for bone disease.
Expression of cannabinoid CB1 and CB2 receptors on osteoclasts. (PDF 102 kb)
Cannabinoid receptor blockade causes apoptosis of mouse and rabbit osteoclasts. (PDF 54 kb)
Bone histomorphometry in CB1 knockout and wild type mice. (PDF 68 kb)
Bone histomorphometry in AM251 treated Ovariectomized mice. (PDF 68 kb)
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Idris, A., van 't Hof, R., Greig, I. et al. Regulation of bone mass, bone loss and osteoclast activity by cannabinoid receptors. Nat Med 11, 774–779 (2005). https://doi.org/10.1038/nm1255
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