Regulation of bone mass, bone loss and osteoclast activity by cannabinoid receptors

Abstract

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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Figure 1: CB1 knockout mice have increased bone mass.
Figure 2: CB1 knockout mice are protected against ovariectomy-induced bone loss.
Figure 3: Regulation of osteoclast formation by cannabinoid receptor ligands.
Figure 4: Osteoclasts (OCL) generated from CB1 knockout mice are resistant to the inhibitory effects of CB1-selective but not CB2-selective receptor antagonists.
Figure 5: Cannabinoid receptor antagonists prevent ovariectomy-induced bone loss.
Figure 6: Cannabinoid receptor antagonists inhibit ERK, c-fos, c-jun and NFATc1 activation in mouse osteoclasts.

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Acknowledgements

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.

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Correspondence to Stuart H Ralston.

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The authors hold patents on the use of cannabinoid receptor ligands as treatments for bone disease.

Supplementary information

Supplementary Fig. 1

Expression of cannabinoid CB1 and CB2 receptors on osteoclasts. (PDF 102 kb)

Supplementary Fig. 2

Cannabinoid receptor blockade causes apoptosis of mouse and rabbit osteoclasts. (PDF 54 kb)

Supplementary Table 1

Bone histomorphometry in CB1 knockout and wild type mice. (PDF 68 kb)

Supplementary Table 2

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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