Background:

Both estrogen deficiency and aging may lead to osteoporosis. Developing novel drugs for treating osteoporosis is a popular research direction. Ataluren (ATA) is a nonaminoglycoside nonsense mutation inhibitor currently used clinically to treat muscular atrophy and Duchenne muscular dystrophy. However, little attention has been given to the role of Ataluren in osteogenesis, and it is unclear whether Ataluren can improve osteogenic differentiation of human- derived bone marrow mesenchymal stem cells (hBMMSCs) and treat osteoporosis.MethodsIn this study, we screened several potential therapeutic agents through a new deep learning-based efficacy prediction system (DLEPS) using transcriptional profiles for osteoporosis. We used ovariectomized (OVX) and aged female C57BL6 mice as bone loss models to demonstrate the role of preventing bone loss for Ataluren. The osteogenic differentiation of hBMMSCs was verified via qRT–PCR, staining and quantification of alkaline phosphatase and alizarin red S, and western blotting (WB), with and without an inhibitor of the BMP-SMAD signaling pathway and siBMP2. ResultsDLEPS screening led to a potential novel drug examinee, ataluren, for treating osteoporosis. Ataluren significantly reversed bone loss in ovariectomized mice. Next, ataluren significantly increased human bone marrow-derived mesenchymal stem cell (hBMMSC) osteogenic differentiation without cytotoxicity, indicated by the high expression index of osteogenic differentiation genes ( OCN , BGLAP , ALP , COL1A , BMP2 , RUNX2 ). Mechanistically, ataluren exerted its function through the BMP–SMAD pathway. Furthermore, it activated SMAD phosphorylation but osteogenic differentiation was attenuated by BMP2–SMAD inhibitors or small interfering RNA of BMP2 . Finally, ataluren significantly reversed bone loss in aged mice. ConclusionsIn summary, our findings suggest that the DLEPS-screened ataluren may be a therapeutic agent against osteoporosis by aiding hBMMSC osteogenic differentiation.