-- Decreases with Age in Mice and Humans and Inhibits Osteoblast Senescence.

Aging is a major risk factor for most chronic diseases, including osteoporosis, and is characterized by an accumulation of senescent cells in various tissues. MicroRNAs (miRNAs) are critical regulators of bone aging and cellular senescence. Here, we report that -- decreases with age in bone samples from mice as well as in posterior iliac crest bone biopsies of younger versus older healthy women. -- also decreased in mouse bone marrow stromal cells following induction of senescence using etoposide, HO, or serial passaging. To explore the transcriptomic effects of --, we performed RNA sequencing of mouse calvarial osteoblasts transfected with control or -- mimics and found that -- overexpression significantly altered the expression of various senescence, senescence-associated secretory phenotype-related, and proliferation genes. Specifically, -- overexpression in nonsenescent osteoblasts significantly suppressed and gene expression and increased their proliferative capacity. Finally, we established a novel senotherapeutic role for this miRNA by treating -- expressing cells with HO to induce senescence. Interestingly, these cells exhibited lower and expression, increased proliferation-related gene expression, and reduced SA-β-Gal+ cells. Our results thus establish that -- is a senescence-associated miRNA that decreases with age in mouse and human bones and is a potential senotherapeutic target for age-related bone loss. © 2023 The Authors. published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.