Meng Fanjin, Zheng Kaiyuan, Deng Meng, Ma Yuwen, Yu Yang, Li Junxiong, Chen Hong, Meng Shan, Guo Bin, Guo Xiaolan, Jiao Li, Zeng Beilei, Yang Chun, Yang Bing, Yin Chong
School of Laboratory Medicine, Translational Medicine Research Center, North Sichuan Medical College, Nanchong, 637000, Sichuan, China.
Department of Clinical Laboratory, Lab of Nucleic Acid Therapy, Department of Oncology, Department of Rehabilitation Medicine, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, Sichuan, China.
Sci Rep. 2025 Jul 1;15(1):20687. doi: 10.1038/s41598-025-05826-z.
Osteoporosis poses a significant threat to human health. Long non-coding RNAs (LncRNAs) have been deemed as crucial regulators in the pathogenesis of osteoporosis. However, the accuracy and efficiency of LncRNA-mediated regulation of bone formation require further improvement. Our previous study identified a repeat sequence in the human-derived LncRNA CTD-2555A7.2, suggesting its potential role in osteoporosis regulation. To investigate this hypothesis, we conducted systematic functional analyses of CTD-2555A7.2 in osteogenesis and explored its mechanisms and potential therapeutic applications. Through over-expression, siRNA silencing and repeat sequence over-expression in vitro and in vivo, our research demonstrate that CTD-2555A7.2 enhances bone formation by sequestering multiple miR-381-3p molecules through its repeat sequence. Through Western blot, siRNA silencing and luciferase reporter assay, we illuminated miR-381-3p suppresses osteogenic differentiation by concurrently targeting four essential genes of the Wnt signaling pathway: Apc, Lef1, wnt5a, and Lrp6. Notably, the mRNA of CTD-2555A7.2 repeat sequence exhibited pronounced therapeutic efficacy in ovariectomy osteoporosis models. Taken together, we identified a dual-amplification osteogenic axis (CTD-2555A7.2-miR-381-Wnt) that demonstrates significant regulatory effects on osteoporosis. This study has established an important theoretical framework for understanding osteogenic LncRNA mechanisms and provides novel insights for developing targeted therapeutics against osteoporosis.
骨质疏松症对人类健康构成重大威胁。长链非编码RNA（LncRNAs）被认为是骨质疏松症发病机制中的关键调节因子。然而，LncRNA介导的骨形成调节的准确性和效率仍需进一步提高。我们之前的研究在人源LncRNA CTD-2555A7.2中鉴定出一个重复序列，提示其在骨质疏松症调节中的潜在作用。为了验证这一假设，我们对CTD-2555A7.2在成骨过程中进行了系统的功能分析，并探索了其作用机制和潜在的治疗应用。通过体外和体内的过表达、siRNA沉默和重复序列过表达，我们的研究表明CTD-2555A7.2通过其重复序列螯合多个miR-381-3p分子来增强骨形成。通过蛋白质免疫印迹、siRNA沉默和荧光素酶报告基因检测，我们阐明了miR-381-3p通过同时靶向Wnt信号通路的四个关键基因Apc、Lef1、wnt5a和Lrp6来抑制成骨分化。值得注意的是，CTD-2555A7.2重复序列的mRNA在去卵巢骨质疏松症模型中表现出显著的治疗效果。综上所述，我们鉴定出了一个双扩增成骨轴（CTD-2555A7.2-miR-381-Wnt），其对骨质疏松症具有显著的调节作用。本研究为理解成骨LncRNA机制建立了重要的理论框架，并为开发针对骨质疏松症的靶向治疗提供了新的见解。
