Carro Vázquez David, Emini Lejla, Rauner Martina, Hofbauer Christine, Skalicky Susanna, Wagner Alisia, Grillari Johannes, Diendorfer Andreas B, Hofbauer Lorenz C, Hackl Matthias
TAmiRNA GmbH, Department of Research and Development, 1110 Vienna, Austria.
Department of Medicine III and Center for Healthy Aging, Technische Universität Dresden Medical Center, 01307 Dresden, Germany.
JBMR Plus. 2024 Sep 17;9(1):ziae121. doi: 10.1093/jbmrpl/ziae121. eCollection 2025 Jan.
Type 2 diabetes mellitus (T2DM) increases the susceptibility of bone fragility. The underlying mechanisms have, however, remained largely unknown. MicroRNAs (miRNAs) are short single-stranded non-coding RNA molecules with utility as biomarkers due to their easy accessibility and stability in bodily fluids. Here, we aimed to use an unbiased approach to identify miRNAs dysregulated in a polygenic mouse model of T2DM. Genome-wide analysis of miRNAs in serum, BM, and bone from the polygenic TallyHo/JngJ (TH) mice, which recapitulate T2DM in humans, was performed. This analysis was compared to the recommended control Swiss Webster Random/Jackson (SWR/J) and a strain-matched non-diabetic control (TH-ND). When comparing TH mice with TH-ND using an adjusted -value false discovery rate (FDR) cut-off of 0.2 to identify differentially expressed miRNAs, mmu-miR-466i-5p and mmu-miR-1195 were found to be up-regulated in both serum and in BM. Dysregulated miRNAs were not found in bone tissue. When comparing TH-ND mice with SWR/J using the same FDR cut-off, mmu-miR-351-5p, and mmu-miR-322-3p were upregulated in both BM and serum, while mmu-miR-449a-5p and mmu-miR-6240 were downregulated in BM and serum. Dysregulated miRNAs in BM or cortical bone compared to serum between TH-ND mice and SWR/J were investigated for their cell-type enrichment to identify putative donor cells and their gene target networks. Gene target network analysis revealed genes involved in diabetes-related signaling pathways as well as in diabetic bone disease. Cell-type enrichment analysis identified hsa-miR-449a enriched in immune cells, hsa-miR-592 in hepatocytes and endothelial cells, while hsa-miR-424-3p, hsa-miR-1-3p, and hsa-miR-196b-5p were enriched in mesenchymal stem cells and their derived tissues. In conclusion, our comparative miRNA profiling sheds light on differential expression patterns between SWR/J and both subgroups of TH. No differences were observed between TH and TH-ND, suggesting the genetic background of SWR/J may be responsible for the change of dysregulated miRNA.
2型糖尿病（T2DM）会增加骨脆性易感性。然而，其潜在机制在很大程度上仍不明确。微小RNA（miRNA）是短的单链非编码RNA分子，因其在体液中易于获取且稳定，具有作为生物标志物的用途。在此，我们旨在采用一种无偏倚的方法，来鉴定在T2DM多基因小鼠模型中失调的miRNA。对在人类中重现T2DM的多基因TallyHo/JngJ（TH）小鼠的血清、骨髓和骨骼中的miRNA进行了全基因组分析。将该分析结果与推荐的对照瑞士韦伯斯特随机/杰克逊（SWR/J）小鼠以及品系匹配的非糖尿病对照（TH-ND）进行了比较。当使用校正后的错误发现率（FDR）临界值0.2比较TH小鼠和TH-ND小鼠以鉴定差异表达的miRNA时，发现mmu-miR-466i-5p和mmu-miR-1195在血清和骨髓中均上调。在骨组织中未发现失调的miRNA。当使用相同的FDR临界值比较TH-ND小鼠和SWR/J小鼠时，mmu-miR-351-5p和mmu-miR-322-3p在骨髓和血清中均上调，而mmu-miR-449a-5p和mmu-miR-6240在骨髓和血清中均下调。研究了TH-ND小鼠和SWR/J小鼠之间骨髓或皮质骨与血清中失调的miRNA的细胞类型富集情况，以鉴定推定的供体细胞及其基因靶标网络。基因靶标网络分析揭示了参与糖尿病相关信号通路以及糖尿病骨病的基因。细胞类型富集分析确定hsa-miR-449a在免疫细胞中富集，hsa-miR-592在肝细胞和内皮细胞中富集，而hsa-miR-424-3p、hsa-miR-1-3p和hsa-miR-196b-5p在间充质干细胞及其衍生组织中富集。总之，我们的比较性miRNA谱分析揭示了SWR/J与TH的两个亚组之间的差异表达模式。在TH和TH-ND之间未观察到差异，这表明SWR/J的遗传背景可能是miRNA失调变化的原因。
