Autophagy in skeletal homeostasis: role in the osteoblast lineage under physiological and stress condition

Throughout life bone is constantly renewed to meet the changes deriving from loading forces and metabolic needs, via the process of bone remodelling. An imbalance in bone remodelling, in favor to bone resorption, results in loss of bone mass and strength, leading to osteoporosis. Multiple factors play a causative role in this process, which include extrinsic (losses of sex steroids, excess of exogenous glucocorticoids, lipid oxidation and marrow adipogenesis, decreased growth factors) and intrinsic (oxidative stress) mechanisms of cell dysfunction. Although these intrinsic mechanisms remain mainly unclear, we hypothesized that autophagy, a recycling-lysosome based pathway, may play a critical role in maintaining bone cells function and viability and that a decline in autophagy with age may be part of the pathogenetic mechanism of age-related skeletal involution. The goals of the study proposed here are to investigate the role of autophagy in bone and to determine whether loss of autophagy in osteocytes increases their susceptibility to stress, such as exogenous glucocorticoids. For these purposes, we inactivated autophagy in osteocytes by conditional deletion of Atg7, a gene essential for autophagy, and found that osteocyte-specific autophagy deficient mice displayed low bone mass and strength, reduced bone turnover and increased oxidative stress. Importantly, all these changes were similar to those that occur with age in wild type mice, suggesting that a decrease in autophagy may contribute to the degenerating effects of aging on the skeleton. To establish whether the autophagy pathway helps osteocytes resist stress, mice lacking autophagy in osteocytes were treated with glucocorticoids (Prednisolone) or placebo for 28 day. Our results demonstrate that exogenous glucocorticoids stimulate autophagic flux in osteocytes in vivo but lack of autophagy in osteocytes does not accentuate the negative impact of glucocorticoids on the skeleton, suggesting that autophagy in this cell type does not appear to be an important defence mechanism opposing the negative effects of glucocorticoids on the skeleton. In conclusion we demonstrated that experimental inactivation of autophagy in osteocytes accelerates skeletal changes associated with aging, but does not accentuate the impact of exogenous glucocorticoids on the skeleton. Overall, these findings identify autophagy as a critical determinant of bone homeostasis and as an intrinsic mechanism to bone cells that contributes to the age-related bone loss, providing a new potential therapeutic target in osteoporosis.