Combined deficiency of the Cnr1 and Cnr2 receptors protects against age-related bone loss by osteoclast inhibition.

Antonia Sophocleous,Aymen I Idris,Dilruba Kabir,Silvia Marino,Stuart H Ralston

doi:10.1111/acel.12638

Abstract

SummaryThe endocannabinoid system plays a role in regulating bone mass and bone cell activity and inactivation of the type 1 (Cnr1) or type 2 (Cnr2) cannabinoid receptors influences peak bone mass and age‐related bone loss. As the Cnr1 and Cnr2 receptors have limited homology and are activated by different ligands, we have evaluated the effects of combined deficiency of Cnr1 and 2 receptors (Cnr1/2−/−) on bone development from birth to old age and studied ovariectomy induced bone loss in female mice. The Cnr1/2−/− mice had accelerated bone accrual at birth when compared with wild type littermates, and by 3 months of age, they had higher trabecular bone mass. They were also significantly protected against ovariectomy‐induced bone loss due to a reduction in osteoclast number. The Cnr1/2−/− mice had reduced age‐related bone loss when compared with wild‐type due to a reduction in osteoclast number. Although bone formation was reduced and bone marrow adiposity increased in Cnr1/2−/− mice, the osteoclast defect outweighed the reduction in bone formation causing preservation of bone mass with aging. This contrasts with the situation previously reported in mice with inactivation of the Cnr1 or Cnr2 receptors individually where aged‐related bone loss was greater than in wild‐type. We conclude that the Cnr1 and Cnr2 receptors have overlapping but nonredundant roles in regulating osteoclast and osteoblast activities. These observations indicate that combined inhibition of Cnr1 and Cnr2 receptors may be beneficial in preventing age‐related bone loss, whereas blockade of individual receptors may be detrimental.

Highlights

Endogenous cannabinoid ligands and their receptors play important roles in the regulation of bone mineral density in animalAccepted for publication 22 May 2017 models of bone disease (Bab et al, 2009; Idris & Ralston, 2012) and in human (Sophocleous et al, 2017)
We and others have reported that female Cnr2 knockout mice develop low bone mass with age due to a decrease in bone formation (Ofek et al, 2006; Sophocleous et al, 2014a,b). These findings demonstrate that both cannabinoid receptors: type 1 (Cnr1) and Cnr2 receptors play a role in bone metabolism but suggest that their effects are to some extent distinct
Body weight is an important determinant of bone mass, and previous studies have shown that both Cnr1 and Cnr2 receptors play a role in the regulation of appetite and body weight (Colombo et al, 1998; Kirkham & Williams, 2001; Cota, 2007; Agudo et al, 2010)

Summary

Introduction

Endogenous cannabinoid (endocannabinoid) ligands and their receptors play important roles in the regulation of bone mineral density in animalAccepted for publication 22 May 2017 models of bone disease (Bab et al, 2009; Idris & Ralston, 2012) and in human (Sophocleous et al, 2017). The endocannabinoid system comprises two known receptors, a family of endogenous ligands and various enzymes that are responsible for ligand synthesis, transport and inactivation Endocannabinoid ligands and their receptors regulate a wide variety of neurological functions including appetite control, pain perception, motor function and the immune response (Matsuda et al, 1990; Idris & Ralston, 2010). Agonists of Cnr and 2 receptors inhibit adenylyl cyclase causing reduction in intracellular levels of cyclic adenosine monophosphate and activation of a variety of downstream signalling pathways including ion channels, Nuclear Factor Kappa-B (NFjB), phosphoinositide kinase, mitogen-activated protein kinase and modulation of second messengers such as ceramide and intracellular calcium (Demuth & Molleman, 2006; Idris & Ralston, 2010)

Results

Discussion

Conclusion