The role of cannabinoid receptors in bone remodeling in a CB1/2 double knockout mouse

This study characterizes the skeletal phenotype in double knockout (dKO) mice using micro‐CT and ex‐vivo analysis. We scanned femurs at ages of 4 weeks to 1 year and compared them to matched controls with parameters of the trabecular and cortical regions. These analyses revealed a complex age‐ and gender‐dependent phenotype. Male and female dKO mice exhibited a significant increase in bone mass at younger ages (4 & 8 weeks). This increase was observed in both trabecular and cortical bone. Male dKO mice demonstrated normalization of trabecular bone mass at 12 and 16 weeks, although cortical bone mass remained increased at these ages. In contrast, trabecular bone mass in female dKO mice remained significantly elevated even up to one year of age. There was the persistence of trabecular bone in the diaphysis of dKO which is consistent with reduced osteoclast function. Ex vivo cultures of bone cells from dKO and normal mice revealed functional abnormalities involving dKO osteoclasts and osteoblasts compared to their normal counterparts. Our results demonstrate the importance of CB1 and CB2 receptors in regulating bone modeling/remodeling. Additional studies will elucidate the mechanisms following CB receptor activation and the signaling pathways affected, which can lead to therapies for the treatment of various forms of osteopenia and to accelerate bone formation which would have a favorable clinical outcome. NIH‐NIAMS AR047432 (to SNP) and The State of PA Department of Health (to FFS).