Circular RNA circStag1 promotes bone regeneration by interacting with HuR

Postmenopausal osteoporosis is a common bone metabolic disorder characterized by deterioration of the bone microarchitecture,leading to an increased risk of fractures.Recently,circular RNAs(circ RNAs)have been demonstrated to play pivotal roles in regulating bone metabolism.However,the underlying functions of circ RNAs in bone metabolism in postmenopausal osteoporosis remain obscure.Here,we report that circ Stag1 is a critical osteoporosis-related circ RNA that shows significantly downregulated expression in osteoporotic bone marrow mesenchymal stem cells(BMSCs)and clinical bone tissue samples from patients with osteoporosis.Overexpression of circ Stag1 significantly promoted the osteogenic capability of BMSCs.Mechanistically,we found that circ Stag1 interacts with human antigen R(Hu R),an RNA-binding protein,and promotes the translocation of Hu R into the cytoplasm.A high cytoplasmic level of Hu R led to the activation of the Wnt signaling pathway by stabilizing and enhancing low-density lipoprotein receptor-related protein 5/6(Lrp5/6)andβ-catenin expression,thereby stimulating the osteogenic differentiation of BMSCs.Furthermore,overexpression of circ Stag1 in vivo by circ Stag1-loaded adeno-associated virus(circ Stag1-AAV)promoted new bone formation,thereby preventing bone loss in ovariectomized rats.Collectively,we show that circ Stag1 plays a pivotal role in promoting the regeneration of bone tissue via Hu R/Wnt signaling,which may provide new strategies to prevent bone metabolic disorders such as postmenopausal osteoporosis.