Aging in bone mesenchymal cells in mice

A decrease in osteoblast number and bone formation are seminal contributors to age-related osteoporosis. However, the aging-associated cellular and molecular mechanisms that impact osteoblast precursors, osteoblasts, and other bone mesenchymal cell types remain unclear. We performed single cell RNA-sequencing of mesenchymal cells present at the endosteum and periosteum of young and old C57BL/6 mice of both sexes to examine how transcriptional programs change in a cell-type specific manner with aging. Transcriptional changes revealed decreased matrix protein production and autophagy, as well as increased senescence, inflammation, and hypoxia. These changes were seen mostly in osteoblast precursors and osteoblasts from the endosteum with greater changes in females. Because mice with deficient macroautophagy in osteoblast lineage cells have low osteoblast number and bone mass, we contrasted the transcriptional changes caused by autophagy depletion with those caused by aging and found several commonalities including increased senescence. Overall, these findings reveal distinct features of aging in males and females and within endosteal versus periosteal cells. Moreover, these results suggest a causal link between declines in autophagy and increased senescence in osteoblastic cells, thereby identifying potential therapeutic targets for osteoporosis.