Reppe Sjur, Reseland Janne Elin, Prijatelj Vid, Prediger Michael, Nogueira Liebert Parreiras, Utheim Tor Paaske, Rivadeneira Fernando, Gautvik Kaare M, Datta Harish Kumar
Department of Medical Biochemistry, Oslo University Hospital, 0450 Oslo, Norway.
Unger-Vetlesen Institute, Lovisenberg Diaconal Hospital, 0456 Oslo, Norway.
Int J Mol Sci. 2024 Nov 27;25(23):12724. doi: 10.3390/ijms252312724.
This study explores how select microRNAs (miRNAs) influence bone structure in humans and in transgenic mice. In trabecular bone biopsies from 84 postmenopausal women (healthy, osteopenic, and osteoporotic), we demonstrate that (deleted in lymphocytic leukemia 2)-encoded is strongly positively associated with bone mineral density (BMD) at different skeletal sites. In bone transcriptome analyses, levels correlated positively with the osteocyte characteristic transcripts (encoding sclerostin) and (Matrix Extracellular Phosphoglycoprotein), while the related showed a negative association with BMD and osteoblast markers. The data imply that these miRNAs have opposite roles in bone remodeling with distinct actions on bone cells. Expression quantitative trait loci (eQTL) variants confirmed earlier associations. Furthermore, a novel variant (rs12585295) showed high localization with transcriptionally active chromatin states in osteoblast primary cell cultures. The supposition that -encoded miRNAs have an important regulatory role in bone remodeling was further confirmed in a transgenic mice model showing that -deleted mice had significantly higher percentage bone volume and trabecular number than the wild type, possibly due to prenatal actions. However, the three-point mechanical break force test of mice femurs showed a positive correlation between strength and levels, indicating differential effects on cortical and trabecular bone. Moreover, these miRNAs appear to have distinct and complex actions in mice prenatally and in adult humans, impacting BMD and microstructure by regulating bone cell transcription. However, detailed interactions between these miRNAs and their downstream mechanisms in health and disease need further clarification.
本研究探讨了特定的微小RNA（miRNA）如何影响人类和转基因小鼠的骨骼结构。在对84名绝经后女性（健康、骨量减少和骨质疏松）的小梁骨活检中，我们证明淋巴细胞白血病缺失2（deleted in lymphocytic leukemia 2，DLEU2）编码的miRNA与不同骨骼部位的骨矿物质密度（BMD）呈强正相关。在骨转录组分析中，DLEU2水平与骨细胞特征转录本（编码硬化蛋白的SOST和基质细胞外磷酸糖蛋白MEPE）呈正相关，而相关的miR-1258则与BMD和成骨细胞标志物呈负相关。数据表明，这些miRNA在骨重塑中具有相反的作用，对骨细胞有不同的作用。表达数量性状位点（eQTL）变异证实了先前的关联。此外，一个新的变异体（rs12585295）在成骨细胞原代细胞培养中与转录活性染色质状态高度定位。在转基因小鼠模型中进一步证实了DLEU2编码的miRNA在骨重塑中具有重要调节作用，该模型显示DLEU2缺失的小鼠的骨体积百分比和小梁数量明显高于野生型，这可能是由于产前作用。然而，小鼠股骨的三点机械断裂力测试表明，强度与DLEU2水平呈正相关，表明对皮质骨和小梁骨有不同的影响。此外，这些miRNA在小鼠产前和成年人类中似乎具有独特而复杂的作用，通过调节骨细胞转录影响BMD和微观结构。然而，这些miRNA与其在健康和疾病中的下游机制之间的详细相互作用需要进一步阐明。
