PNAS | January 17, 2006 | vol. 103 | no. 3 | 696-701
MEDICAL SCIENCES
Peripheral cannabinoid receptor, CB2, regulates bone mass
*Bone Laboratory and Departments of ¶Pharmacology and ||Medicinal Chemistry and Natural Products, Hebrew University of Jerusalem, Jerusalem 91120, Israel; Department of Psychiatry, Life and Brain Center, University of Bonn, 53105 Bonn, Germany; Department of Orthopaedic Surgery, Institute for Genetic Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA 90033; and Department of Pharmacology, University of Bath, Bath BA2 7AY, United Kingdom
The endogenous cannabinoids bind to and activate two G protein-coupled receptors, the predominantly central cannabinoid receptor type 1 (CB1) and peripheral cannabinoid receptor type 2 (CB2). Whereas CB1 mediates the cannabinoid psychotropic, analgesic, and orectic effects, CB2 has been implicated recently in the regulation of liver fibrosis and atherosclerosis. Here we show that CB2-deficient mice have a markedly accelerated age-related trabecular bone loss and cortical expansion, although cortical thickness remains unaltered. These changes are reminiscent of human osteoporosis and may result from differential regulation of trabecular and cortical bone remodeling. The CB2–/– phenotype is also characterized by increased activity of trabecular osteoblasts (bone-forming cells), increased osteoclast (the bone-resorbing cell) number, and a markedly decreased number of diaphyseal osteoblast precursors. CB2 is expressed in osteoblasts, osteocytes, and osteoclasts. A CB2-specific agonist that does not have any psychotropic effects enhances endocortical osteoblast number and activity and restrains trabecular osteoclastogenesis, apparently by inhibiting proliferation of osteoclast precursors and receptor activator of NF-
B ligand expression in bone marrow-derived osteoblasts/stromal cells. The same agonist attenuates ovariectomy-induced bone loss and markedly stimulates cortical thickness through the respective suppression of osteoclast number and stimulation of endocortical bone formation. These results demonstrate that the endocannabinoid system is essential for the maintenance of normal bone mass by osteoblastic and osteoclastic CB2 signaling. Hence, CB2 offers a molecular target for the diagnosis and treatment of osteoporosis, the most prevalent degenerative disease in developed countries.
bone remodeling | HU-308 | osteoblast | osteoclast
The endogenous cannabinoids bind to and activate the cannabinoid receptors 1 and 2 (CB1 and CB2, respectively). Both are seven-transmembrane domain receptors, and they share 44% identity. They are coupled to the inhibitory guanine nucleotide-binding regulatory protein subclass of G proteins and inhibit stimulated adenylyl cyclase activity (1). That CB1 and CB2 are not functionally identical is demonstrated by the selective regulation of ion channels by only CB1 (2). CB1 is present in the brain and in peripheral neurons and accounts for most of the actions of cannabinoid drugs and endocannabinoids on the central nervous system (3, 4). CB2 was reported in the immune system (5), in liver cirrhosis (6), and in atherosclerotic plaques (7).
In vertebrates, bone mass and shape are determined by continuous remodeling consisting of the concerted and balanced action of osteoclasts, the bone-resorbing cells, and osteoblasts, the bone-forming cells. Osteoporosis, the most prevalent degenerative disease in developed countries, results from the impairment of this balance, leading to bone loss and increased fracture risk. It has been recently reported that bone remodeling is subject to central control through pathways that involve signaling by the hypothalamic receptors for leptin and neuropeptide Y (8, 9), which are also associated with the regulation of endocannabinoid brain levels (10). These observations led us to assess the role of the endocannabinoid signaling system in the regulation of bone mass. Indeed, we demonstrate here a low bone mass phenotype in mice deficient for the peripheral cannabinoid receptor (CB2), which is normally expressed in osteoblasts, osteoclasts, and their precursors. A CB2-specific agonist, which has no psychotropic or other central effects, regulates the activity of these cells and attenuates ovariectomy (OVX)-induced bone loss. These data suggest an important regulatory role of the endocannabinoid system in bone and offer molecular targets for the development of diagnostic and therapeutic approaches to osteoporosis.