雌激素缺乏和衰老都可能导致骨质疏松症。开发治疗骨质疏松的新药是一个热门的研究方向。我们通过一种新的基于深度学习的疗效预测系统（DLEPS）使用骨质疏松症的转录谱筛选了几种潜在的治疗药物。DLEPS筛查导致潜在的新型药物考生，Ataluren,用于治疗骨质疏松症。Ataluren可显着逆转卵巢切除小鼠的骨丢失。接下来,ataluren显著增加人骨髓间充质干细胞（hBMMSC）成骨分化而无细胞毒性，成骨分化基因的高表达指数(OCN，BGLAP,ALP,COL1A,BMP2,RUNX2)。机械上,ataluren通过BMP-SMAD途径发挥其功能。此外，它激活了SMAD磷酸化，但BMP2-SMAD抑制剂或BMP2的小干扰RNA减弱了成骨分化。最后,ataluren可显着逆转老年小鼠的骨丢失。总之,我们的研究结果表明,DLEPS筛选的ataluren可能通过帮助hBMMSC成骨分化而成为骨质疏松症的治疗药物.
Both estrogen deficiency and aging may lead to osteoporosis. Developing novel drugs for treating osteoporosis is a popular research direction. We screened several potential therapeutic agents through a new deep learning-based efficacy prediction system (DLEPS) using transcriptional profiles for osteoporosis. DLEPS 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. In summary, our findings suggest that the DLEPS-screened
ataluren may be a therapeutic agent against osteoporosis by aiding hBMMSC osteogenic differentiation.
