Beccacece Livia, Pallotti Stefano, Li Yiyun, Huang Jie, Pasotti Leonardo, Napolioni Valerio
Genomic And Molecular Epidemiology (GAME) Lab, School of Biosciences and Veterinary Medicine, University of Camerino, Via Gentile da Varano III, Camerino, 62032, Italy.
School of Public Health and Emergency Medicine, Southern University of Science and Technology, Shenzhen, China.
BMC Genomics. 2025 May 23;26(1):524. doi: 10.1186/s12864-025-11702-x.
The Anterior Cruciate Ligament (ACL) plays a critical role in maintaining the musculoskeletal stability of the knee. Its injury has been linked to an increased risk of developing osteoarthritis. This study aims to identify cross-species responses to ACL rupture providing insights on its molecular basis. We analyzed five publicly available transcriptomic datasets from Homo sapiens, Mus musculus, Canis lupus familiaris, and Oryctolagus cuniculus. Differential gene expression analysis was performed for each dataset, producing a genome-wide transcriptional signature of fold-change significance for individual genes. Stouffer's method was used to integrate the results, identifying genes significantly deregulated across all species. Additionally, gene-set enrichment analysis revealed pathways that were consistently upregulated or downregulated.
A positive correlation in expression was observed between human and the other three species (r = 0.177-0.305, p-value ≤ 2.7 × 10), identifying 210 genes as the most consistently up- and down-regulated in response to ACL rupture (p-adjusted ≤ 1.27 × 10). These genes are primarily involved in cellular mitosis, collagen pathways, and cartilage development. Furthermore, 60 pathways were found to be significantly up- or down-regulated across all species (p-adjusted ≤ 4.57 × 10). Among these, the upregulation of inhibition of bone mineralization (p-adjusted ≤ 2.99 × 10) aligns with previous findings on the reduction of subchondral bone mineral density following ACL rupture.
This study highlights that distinct species exhibit common molecular responses to ACL rupture, underscoring the value of mice, dogs, and rabbits as potential translational model organisms for ACL rupture research. Furthermore, the identified genes and pathways highlight the molecular mechanisms underlying ACL rupture.
前交叉韧带（ACL）在维持膝关节的肌肉骨骼稳定性方面起着关键作用。其损伤与患骨关节炎的风险增加有关。本研究旨在确定对ACL断裂的跨物种反应，以深入了解其分子基础。我们分析了来自智人、小家鼠、家犬和穴兔的五个公开可用的转录组数据集。对每个数据集进行差异基因表达分析，生成单个基因的全基因组转录特征，以倍数变化的显著性表示。采用斯托弗方法整合结果，确定在所有物种中均显著失调的基因。此外，基因集富集分析揭示了持续上调或下调的通路。
观察到人类与其他三个物种之间在表达上呈正相关（r = 0.177 - 0.305，p值≤2.7×10），确定了210个基因是对ACL断裂反应中最一致上调和下调的基因（p值调整后≤1.27×10）。这些基因主要参与细胞有丝分裂、胶原蛋白通路和软骨发育。此外，发现60条通路在所有物种中均显著上调或下调（p值调整后≤4.57×10）。其中，骨矿化抑制的上调（p值调整后≤2.99×10）与先前关于ACL断裂后软骨下骨矿物质密度降低的研究结果一致。
本研究强调不同物种对ACL断裂表现出共同的分子反应，凸显了小鼠、狗和兔子作为ACL断裂研究潜在转化模型生物的价值。此外，鉴定出的基因和通路突出了ACL断裂背后的分子机制。
