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 (circRNAs) have been demonstrated to play pivotal roles in regulating bone metabolism. However, the underlying functions of circRNAs in bone metabolism in postmenopausal osteoporosis remain obscure. Here, we report that circStag1 is a critical osteoporosis-related circRNA that shows significantly downregulated expression in osteoporotic bone marrow mesenchymal stem cells (BMSCs) and clinical bone tissue samples from patients with osteoporosis. Overexpression of circStag1 significantly promoted the osteogenic capability of BMSCs. Mechanistically, we found that circStag1 interacts with human antigen R (HuR), an RNA-binding protein, and promotes the translocation of HuR into the cytoplasm. A high cytoplasmic level of HuR led to the activation of the Wnt signaling pathway by stabilizing and enhancing low-density lipoprotein receptor-related protein 5/6 (Lrp5/6) and β-catenin expression, thereby stimulating the osteogenic differentiation of BMSCs. Furthermore, overexpression of circStag1 in vivo by circStag1-loaded adeno-associated virus (circStag1-AAV) promoted new bone formation, thereby preventing bone loss in ovariectomized rats. Collectively, we show that circStag1 plays a pivotal role in promoting the regeneration of bone tissue via HuR/Wnt signaling, which may provide new strategies to prevent bone metabolic disorders such as postmenopausal osteoporosis.

绝经后骨质疏松症是一种常见的骨代谢紊乱，其特征是骨微结构恶化，导致骨折风险增加。最近，环状RNA（circRNA）已被证明在调节骨代谢中发挥着关键作用。然而，circRNA 在绝经后骨质疏松症骨代谢中的潜在功能仍不清楚。在这里，我们报道了 circStag1 是一种与骨质疏松症相关的关键 circRNA，在骨质疏松症骨髓间充质干细胞 (BMSC) 和骨质疏松症患者的临床骨组织样本中表现出显着下调的表达。 circStag1的过度表达显着促进BMSCs的成骨能力。从机制上讲，我们发现 circStag1 与人类抗原 R (HuR)（一种 RNA 结合蛋白）相互作用，并促进 HuR 易位到细胞质中。细胞质中高水平的HuR通过稳定和增强低密度脂蛋白受体相关蛋白5/6（ Lrp5/6）和β-catenin的表达来激活Wnt信号通路，从而刺激BMSCs的成骨分化。此外，负载circStag1的腺相关病毒（circStag1-AAV）在体内过度表达circStag1可促进新骨形成，从而防止卵巢切除大鼠的骨质流失。总的来说，我们发现circStag1通过HuR/Wnt信号传导在促进骨组织再生方面发挥着关键作用，这可能为预防绝经后骨质疏松症等骨代谢紊乱提供新策略。