Table_1_Metabolic Signature of Articular Cartilage Following Mechanical Injury: An Integrated Transcriptomics and Metabolomics Analysis.xlsx

Mechanical injury to the articular cartilage is a key risk factor in joint damage and predisposition to osteoarthritis. Integrative multi-omics approaches provide a valuable tool to understand tissue behavior in response to mechanical injury insult and help to identify key pathways linking injury to tissue damage. Global or untargeted metabolomics provides a comprehensive characterization of the metabolite content of biological samples. In this study, we aimed to identify the metabolic signature of cartilage tissue post injury. We employed an integrative analysis of transcriptomics and global metabolomics of murine epiphyseal hip cartilage before and after injury. Transcriptomics analysis showed a significant enrichment of gene sets involved in regulation of metabolic processes including carbon metabolism, biosynthesis of amino acids, and steroid biosynthesis. Integrative analysis of enriched genes with putatively identified metabolite features post injury showed a significant enrichment for carbohydrate metabolism (glycolysis, galactose, and glycosylate metabolism and pentose phosphate pathway) and amino acid metabolism (arginine biosynthesis and tyrosine, glycine, serine, threonine, and arginine and proline metabolism). We then performed a cross analysis of global metabolomics profiles of murine and porcine ex vivo cartilage injury models. The top commonly modulated metabolic pathways post injury included arginine and proline metabolism, arginine biosynthesis, glycolysis/gluconeogenesis, and vitamin B6 metabolic pathways. These results highlight the significant modulation of metabolic responses following mechanical injury to articular cartilage. Further investigation of these pathways would provide new insights into the role of the early metabolic state of articular cartilage post injury in promoting tissue damage and its link to disease progression of osteoarthritis.

关节软骨机械损伤是关节退变及骨关节炎（osteoarthritis）易感性的关键风险因素。整合多组学（integrative multi-omics）策略为解析组织在机械损伤刺激下的应答行为特征提供了重要工具，同时助力明确连接损伤与组织退变的核心通路。全局或非靶向代谢组学（global or untargeted metabolomics）可全面表征生物样本中的代谢物组成。本研究旨在明确损伤后软骨组织的代谢特征。我们针对小鼠骨骺髋部软骨损伤前后的转录组学（transcriptomics）与全局代谢组学数据开展整合分析。转录组学分析显示，代谢过程调控相关基因集显著富集，涵盖碳代谢、氨基酸生物合成及类固醇生物合成等通路。将富集基因与损伤后疑似鉴定的代谢物特征进行整合分析，结果显示碳水化合物代谢（糖酵解、半乳糖代谢、糖基化代谢及磷酸戊糖通路）与氨基酸代谢（精氨酸生物合成，以及酪氨酸、甘氨酸、丝氨酸、苏氨酸及精氨酸与脯氨酸代谢）通路显著富集。随后我们对小鼠与猪离体（ex vivo）软骨损伤模型的全局代谢组学图谱开展交叉分析。损伤后共同调控的核心代谢通路包括精氨酸与脯氨酸代谢、精氨酸生物合成、糖酵解/糖异生及维生素B6代谢通路。上述结果表明，关节软骨机械损伤后代谢应答存在显著调控变化。进一步探究上述通路，可为揭示损伤早期关节软骨代谢状态在促进组织退变及其与骨关节炎疾病进展关联中的作用提供新视角。