PGC1 Organizes the Osteoclast Cytoskeleton by Mitochondrial Biogenesis and Activation

Osteoclasts are mitochondria-rich cells, but the role of these energy-producing organelles in bone resorption is poorly defined. To this end, we conditionally deleted the mitochondria-inducing co-activator, PGC1, in myeloid lineage cells to generate PGC1(LysM) mice. In contrast to previous reports, PGC1-deficient macrophages differentiate normally into osteoclasts albeit with impaired resorptive function due to cytoskeletal disorganization. Consequently, bone mass of PGC1(LysM) mice is double that of wild type. Mitochondrial biogenesis and function are diminished in PGC1(LysM) osteoclasts. All abnormalities are normalized by PGC1 transduction. Furthermore, OXPHOS inhibitors reproduce the phenotype of PGC1 deletion. PGC1's organization of the osteoclast cytoskeleton is mediated by expression of GIT1, which also promotes mitochondrial biogenesis. Thus, osteoclast mitochondria regulate the cell's resorptive activity by promoting cytoskeletal organization. (c) 2018 American Society for Bone and Mineral Research.