Involvement of Neuronal Cannabinoid Receptor CB1 in Regulation of Bone Mass and Bone Remodeling

The CB1 cannabinoid receptor has been implicated in the regulation of bone remodeling and bone mass. A high bone mass (HBM) phenotype was reported in CB1-null mice generated on a CD1 background (CD1^CB1-/- mice). By contrast, our preliminary studies in cb1^-/- mice, backcrossed to C57BL/6J mice (C57^CB1-/- mice), revealed low bone mass (LBM). We therefore analyzed CB1 expression in bone and compared the skeletons of sexually mature C57^CB1-/- and CD1^CB1-/- mice in the same experimental setting. CB1 mRNA is weakly expressed in osteoclasts and immunoreactive CB1 is present in sympathetic neurons, close to osteoblasts. In addition to their LBM, male and female C57^CB1-/- mice exhibit decreased bone formation rate and increased osteoclast number. The skeletal phenotype of the CD1^CB1-/- mice shows a gender disparity. Female mice have normal trabecular bone with a slight cortical expansion, whereas male CD1^CB1-/- animals display an HBM phenotype. We were surprised to find that bone formation and resorption are within normal limits. These findings, at least the consistent set of data obtained in the C57^CB1-/- line, suggest an important role for CB1 signaling in the regulation of bone remodeling and bone mass. Because sympathetic CB1 signaling inhibits norepinephrine (NE) release in peripheral tissues, part of the endocannabinoid activity in bone may be attributed to the regulation of NE release from sympathetic nerve fibers. Several phenotypic discrepancies have been reported between C57^CB1-/- and CD1^CB1-/- mice that could result from genetic differences between the background strains. Unraveling these differences can provide useful information on the physiologic functional milieu of CB1 in bone.