Regulation of Bone Mass, Osteoclast Function, and Ovariectomy-Induced Bone Loss by the Type 2 Cannabinoid Receptor
The endocannabinoid system has recently been shown to play a role in the regulation of bone metabolism. The type 2 cannabinoid receptor (CB2) has been reported to regulate bone mass, but conflicting results have been reported with regard to its effects on bone resorption and osteoclast function. Her...
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Published in | Endocrinology (Philadelphia) Vol. 149; no. 11; pp. 5619 - 5626 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
Bethesda, MD
Endocrine Society
01.11.2008
Oxford University Press |
Subjects | |
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Abstract | The endocannabinoid system has recently been shown to play a role in the regulation of bone metabolism. The type 2 cannabinoid receptor (CB2) has been reported to regulate bone mass, but conflicting results have been reported with regard to its effects on bone resorption and osteoclast function. Here we investigated the role that CB2 plays in regulating bone mass and osteoclast function using a combination of pharmacological and genetic approaches. The CB2-selective antagonist/inverse agonist AM630 inhibited osteoclast formation and activity in vitro, whereas the CB2-selective agonists JWH133 and HU308 stimulated osteoclast formation. Osteoclasts generated from CB2 knockout mice (CB2−/−) were resistant to the inhibitory effects of AM630 in vitro, consistent with a CB2-mediated effect. There was no significant difference in peak bone mass between CB2−/− mice and wild-type littermates, but after ovariectomy, bone was lost to a greater extent in wild-type compared with CB2−/− mice. Furthermore, AM630 protected against bone loss in wild-type mice, but the effect was blunted in CB2−/− mice. We conclude that CB2 regulates osteoclast formation and bone resorption in vitro and that under conditions of increased bone turnover, such as after ovariectomy, CB2 regulates bone loss. These observations indicate that CB2 regulates osteoclast formation and contributes to ovariectomy-induced bone loss and demonstrate that cannabinoid receptor antagonists/inverse agonists may be of value in the treatment of bone diseases characterized by increased osteoclast activity. |
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AbstractList | The endocannabinoid system has recently been shown to play a role in the regulation of bone metabolism. The type 2 cannabinoid receptor (CB2) has been reported to regulate bone mass, but conflicting results have been reported with regard to its effects on bone resorption and osteoclast function. Here we investigated the role that CB2 plays in regulating bone mass and osteoclast function using a combination of pharmacological and genetic approaches. The CB2-selective antagonist/inverse agonist AM630 inhibited osteoclast formation and activity in vitro, whereas the CB2-selective agonists JWH133 and HU308 stimulated osteoclast formation. Osteoclasts generated from CB2 knockout mice (CB2−/−) were resistant to the inhibitory effects of AM630 in vitro, consistent with a CB2-mediated effect. There was no significant difference in peak bone mass between CB2−/− mice and wild-type littermates, but after ovariectomy, bone was lost to a greater extent in wild-type compared with CB2−/− mice. Furthermore, AM630 protected against bone loss in wild-type mice, but the effect was blunted in CB2−/− mice. We conclude that CB2 regulates osteoclast formation and bone resorption in vitro and that under conditions of increased bone turnover, such as after ovariectomy, CB2 regulates bone loss. These observations indicate that CB2 regulates osteoclast formation and contributes to ovariectomy-induced bone loss and demonstrate that cannabinoid receptor antagonists/inverse agonists may be of value in the treatment of bone diseases characterized by increased osteoclast activity. The endocannabinoid system has recently been shown to play a role in the regulation of bone metabolism. The type 2 cannabinoid receptor (CB2) has been reported to regulate bone mass, but conflicting results have been reported with regard to its effects on bone resorption and osteoclast function. Here we investigated the role that CB2 plays in regulating bone mass and osteoclast function using a combination of pharmacological and genetic approaches. The CB2-selective antagonist/inverse agonist AM630 inhibited osteoclast formation and activity in vitro, whereas the CB2-selective agonists JWH133 and HU308 stimulated osteoclast formation. Osteoclasts generated from CB2 knockout mice (CB2-/-) were resistant to the inhibitory effects of AM630 in vitro, consistent with a CB2-mediated effect. There was no significant difference in peak bone mass between CB2-/- mice and wild-type littermates, but after ovariectomy, bone was lost to a greater extent in wild-type compared with CB2-/- mice. Furthermore, AM630 protected against bone loss in wild-type mice, but the effect was blunted in CB2-/- mice. We conclude that CB2 regulates osteoclast formation and bone resorption in vitro and that under conditions of increased bone turnover, such as after ovariectomy, CB2 regulates bone loss. These observations indicate that CB2 regulates osteoclast formation and contributes to ovariectomy-induced bone loss and demonstrate that cannabinoid receptor antagonists/inverse agonists may be of value in the treatment of bone diseases characterized by increased osteoclast activity. |
Author | Ralston, Stuart H Idris, Aymen I Sophocleous, Antonia van't Hof, Robert J Landao-Bassonga, Euphemie |
Author_xml | – sequence: 1 givenname: Aymen I surname: Idris fullname: Idris, Aymen I – sequence: 2 givenname: Antonia surname: Sophocleous fullname: Sophocleous, Antonia – sequence: 3 givenname: Euphemie surname: Landao-Bassonga fullname: Landao-Bassonga, Euphemie – sequence: 4 givenname: Robert J surname: van't Hof fullname: van't Hof, Robert J – sequence: 5 givenname: Stuart H surname: Ralston fullname: Ralston, Stuart H |
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Keywords | Osteoarticular system Bone mass Ovariectomy Cannabinoid receptor Diseases of the osteoarticular system Osteoclast Bone Osteopenia |
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SubjectTerms | Animals Biological and medical sciences Bone and Bones - anatomy & histology Bone Density - genetics Bone diseases Bone growth Bone loss Bone Marrow Cells - drug effects Bone mass Bone resorption Bone Resorption - etiology Bone Resorption - genetics Bone turnover Cannabinoid CB2 receptors Cannabinoids - pharmacology Cells, Cultured Coculture Techniques Diseases of the osteoarticular system Drug Evaluation, Preclinical Drug Inverse Agonism Endocannabinoid system Female Fundamental and applied biological sciences. Psychology Indoles - pharmacology Inverse agonists Medical sciences Mice Mice, Inbred C57BL Mice, Knockout Oophorectomy Organ Size - genetics Osteoclasts Osteoclasts - drug effects Osteoclasts - metabolism Osteoclasts - physiology Osteoporosis. Osteomalacia. Paget disease Ovariectomy Ovariectomy - adverse effects Piperidines - pharmacology Pyrazoles - pharmacology Receptor, Cannabinoid, CB2 - agonists Receptor, Cannabinoid, CB2 - antagonists & inhibitors Receptor, Cannabinoid, CB2 - genetics Receptor, Cannabinoid, CB2 - physiology Receptors Vertebrates: endocrinology |
Title | Regulation of Bone Mass, Osteoclast Function, and Ovariectomy-Induced Bone Loss by the Type 2 Cannabinoid Receptor |
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