AMPKα1 negatively regulates osteoclastogenesis and mitigate pathological bone loss

Osteoclasts are specialized cells in the human body responsible for bone resorption, a highly energy-demanding process. Focus on osteoclast metabolism could be a key for the treatment of osteolytic diseases including osteoporosis. In this context, AMPKα1, an energy sensor highly expressed in osteoclasts, participates in the metabolic reconfiguration during osteoclast differentiation and activation. This study aimed to elucidate the role of AMPKα1 during osteoclastogenesis in vitro and its impact in bone loss in vivo. Using LysMcre/0AMPK⍺1f/f animals, and their respective LysMcre/0 controls we evaluated how AMPKα1 interferes with osteoclastogenesis and bone resorption activity in vitro. We found that AMPKα1 is highly expressed in the early stages of osteoclastogenesis. Genetic deletion of AMPKα1 leads to increased gene expression of osteoclast differentiation and fusion markers such as Nfatc1, Dcstamp. In addition, LysMcre/0AMPK⍺1f/f mice had an increased number and size of differentiated osteoclast. Accordingly, our data suggest that AMPKα1 negatively regulates bone resorption in vitro, as evidenced by the elevated expression of Ctsk and Mmp9 along with an increase in the area of bone resorption in LysMcre/0AMPK⍺1f/f osteoclasts. Our data further demonstrated that AMPKα1 regulates mitochondrial fusion and fission markers upregulating Mfn2 and downregulating DRP1, and that Ctskcre/0AMPK⍺1f/f osteoclasts ultimately leading to an increase in the number of mitochondria in AMPK⍺1 deficient osteoclast. In our in vivo study, femurs from Ctskcre/0AMPK⍺1f/f animals exhibited bone loss associated with the increased number of osteoclasts. Interestingly, in the ovariectomy model, no significant difference in bone loss was observed between Ctskcre/0AMPK⍺1f/f ovariectomized and Sham groups. Our data suggest that AMPKα1 act as a negative regulator of osteoclastogenesis, and the depletion of AMPKα1 in osteoclast leads to a bone loss state similar to that observed after ovariectomy.