Mitochondrial oxidative stress or decreased autophagy in osteoblast lineage cells is not sufficient to mimic the deleterious effects of aging on bone mechanoresponsiveness.

Exercise-induced mechanical load stimulates bone cells, including osteocytes, to promote bone formation. The bone response to loading is less effective with aging, but the cellular and molecular mechanisms responsible for the impaired mechanoresponsiveness remain unclear. Excessive mitochondrial reactive oxygen species (mtROS) and deficient autophagy are common aging mechanisms implicated in decreased bone formation in old mice. Here, we confirmed that the osteogenic effects of tibia compressive loading are lower in old versus young female mice. We also examined whether an increase in mtROS or decreased autophagy in osteoblast-lineage cells of adult female mice could mimic the deleterious effects of aging. To this end, we loaded mice lacking the antioxidant enzyme superoxide dismutase 2 (Sod2) or autophagy-related 7 (Atg7) in cells targeted by Osterix1 (Osx1)-Cre. Osteocytes in Atg7(Δ)(Osx1) exhibited altered morphology and decreased osteocyte dendrite projections. Two weeks of loading increased cortical bone mass and bone formation rate at both periosteal and endosteal surfaces of Osx1-Cre control mice. Nonetheless, in both Atg7(Δ)(Osx1) and Sod2(Δ)(Osx1) mice the response to loading was identical to that observed in control mice, indicating that compromised Atg7-dependent autophagy or excessive mtROS are not sufficient to impair the bone response to tibial compressive loading. Thus, alternative mechanisms of aging might be responsible for the decreased response of the aged skeleton to mechanical stimuli. These findings also suggest that an intact osteocyte dendrite network is not required for the osteogenic response in this model of bone loading.