Mechano-sensitive long noncoding RNA AK091765 inhibits bone formation via microRNA-489-3p binding

Mechanical stimuli are essential factors which maintain bone homeostasis. A lack of mechanical stress is the main cause of osteoporosis in astronauts in space and also aged individuals. However, the molecular mechanisms whereby mechanical stimuli regulate bone formation remain poorly understood. Recent investigations have shown that long noncoding RNAs (LncRNAs) are important regulators of bone formation under different mechanical conditions. We previously reported a mouse derived Lnc-DIF (Differentiation Inhibiting Factor) as a negative regulator in osteoblast differentiation. In this study, we identified AK091765 as a human derived LncRNA with high sequence similarity to Lnc-DIF. Functional analyses indicated that both molecules were mechanosensitive and inhibited bone formation under mechanical unloading by sequestering the miR-489-3p/SMAD2 axis. Moreover, recombinant small interfering RNAs (siRNAs) targeting Lnc-DIF and AK091765 showed therapeutic potential in osteogenic differentiation caused by mechanical unloading. These results provide important evidence for RNA-based osteoporosis therapy.