Beneficial effects of anti-RANKL antibody in depression-like phenotype, inflammatory bone markers, and bone mineral density in male susceptible mice after chronic social defeat stress.

ABSTRACT

Multiple lines of evidence suggest a link between depression and osteoporosis in elderly people. Receptor activator of nuclear factor-κB ligand (RANKL) plays a role in the pathology of osteoporosis, and anti-RANKL antibody has been used in the treatment of osteoporosis. In this study, we investigated whether anti-mouse RANKL antibody could attenuate depression-like phenotypes, inflammatory bone markers and bone mineral density (BMD) in male susceptible mice after chronic social defeat stress (CSDS). We measured plasma levels of inflammatory bone markers, including osteoprotegerin (OPG), RANKL, and osteopontin. A single intravenous injection of anti-RANKL (2 mg/kg) elicited rapid antidepressant effects in CSDS susceptible mice. Furthermore, anti-RANKL significantly improved the increased plasma levels of RANKL and decreased OPG/RANKL ratio in CSDS susceptible mice. Moreover, anti-RANKL significantly attenuated the decreased BMD in CSDS susceptible mice. Interestingly, there is a positive correlation between anhedonia-like behavior and OPG/RANKL ratio in mice. These findings demonstrate that anti-RANKL may have beneficial effects in depression-like phenotype and abnormalities in bone functions of CSDS susceptible mice. It is, therefore, likely that anti-human RANKL antibody (i.e., Denosumab) would be a potential therapeutic drug for depression and osteoporosis.