Genetic Deletion of Catalytic Subunits of AMP-activated Protein Kinase Increases Osteoclasts and Reduces Bone Mass in Young Adult Mice

AMP-activated protein kinase (AMPK) is a key regulator of cellular and systemic energy homeostasis and a potential therapeutic target for the intervention of cancer and metabolic disorders. However, the role of AMPK in bone homeostasis remains incompletely understood. Here we assessed the skeletal phenotype of mice lacking catalytic subunits of AMPK and found that mice lacking AMPK alpha 1 (Prkaa1(-/-)) or AMPK alpha 2 (Prkaa2(-/-)) had reduced bone mass compared with the WT mice, although the reduction was less in Prkaa2(-/-) mice than in Prkaa1(-/-) mice. Static and dynamic bone histomorphometric analyses revealed that Prkaa1(-/-) mice had an elevated rate of bone remodeling because of increases in bone formation and resorption, whereas AMPK alpha 2 KO-induced bone mass reduction was largely attributable to elevated bone resorption. In agreement with our in vivo results, AMPK alpha deficiency was associated with increased osteoclastogenesis in vitro. Moreover, we found that AMPK alpha 1 inhibited the receptor activator of nuclear factor kappa B (RANK) signaling, providing an explanation for AMPK-mediated inhibition of osteoclastogenesis. Therefore, our findings further underscore the importance of AMPKin bone homeostasis, in particular osteoclastogenesis, in young adult mammals.