Ma Guixing, Cheng Siyuan, Han Yingying, Tang Wanze, Pang Wei, Chen Litong, Ding Zhen, Cao Huiling
Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Key University Laboratory of Metabolism and Health of Guangdong, Southern University of Science and Technology, Shenzhen 518055, China.
Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Key University Laboratory of Metabolism and Health of Guangdong, Southern University of Science and Technology, Shenzhen 518055, China.
Mol Ther. 2025 Feb 5;33(2):631-648. doi: 10.1016/j.ymthe.2024.12.046. Epub 2024 Dec 31.
Our study elucidates the crucial role of the liver in bone homeostasis through the p53-miR17 family (miR17-miR20/miR20-miR106/miR93-miR106)-Rankl axis. We demonstrate the enhanced hepatocyte Rankl expression in inflammaging conditions, such as aging, ovariectomized (OVX) mice, and elderly humans. Mice with hepatocyte-specific Rankl deletion exhibit significant resistance to bone mass loss associated with aging, lipopolysaccharide (LPS)-induced inflammation, or estrogen deficiency, compared with controls. Our study highlights hepatocytes as the primary source of Rankl in the liver and serum under these conditions. We identify the p53-miR17 family axis as a crucial regulator for hepatocyte Rankl expression, with p53 inhibiting the miR17 family transcription. Through bioinformatics analysis and in vitro validation, we identify Rankl mRNA as a direct target of the miR17 family. Targeting this axis via CasRx-mediated mRNA editing or miRNA interference significantly attenuates bone mass loss in mice. Our investigation underscores the pivotal significance and therapeutic potential of modulating the p53-miR17 family-Rankl axis in the treatment of inflammaging-associated osteoporosis.
我们的研究阐明了肝脏通过p53- miR17家族（miR17- miR20/miR20- miR106/miR93- miR106）-Rankl轴在骨稳态中的关键作用。我们证明，在衰老、去卵巢（OVX）小鼠和老年人等炎症衰老条件下，肝细胞Rankl表达增强。与对照组相比，肝细胞特异性缺失Rankl的小鼠对与衰老、脂多糖（LPS）诱导的炎症或雌激素缺乏相关的骨质流失具有显著抗性。我们的研究强调，在这些条件下，肝细胞是肝脏和血清中Rankl的主要来源。我们确定p53- miR17家族轴是肝细胞Rankl表达的关键调节因子，p53抑制miR17家族转录。通过生物信息学分析和体外验证，我们确定Rankl mRNA是miR17家族的直接靶点。通过CasRx介导的mRNA编辑或miRNA干扰靶向该轴可显著减轻小鼠的骨质流失。我们的研究强调了调节p53- miR17家族-Rankl轴在治疗炎症衰老相关骨质疏松症中的关键意义和治疗潜力。
