Translational efforts in osteoarthritis are hampered by a gap in our understanding of disease processes at the molecular level. Here, we present evidence of pronounced transcriptional changes in high- and low-disease-grade cartilage tissue, pointing to embryonic processes involved in disease progression. We identify shared transcriptional programs between osteoarthritis cartilage and cell populations in the human embryonic and fetal limb, pointing to increases in pre-hypertrophic chondrocytes’ transcriptional programs in low-grade cartilage and increases in osteoblastic signatures in high-grade disease tissue. We find that osteoarthritis genetic risk signals are enriched in six gene co-expression modules and show that these transcriptional signatures reflect cell-type-specific expression along the endochondral ossification developmental trajectory. Using this network approach in combination with causal inference analysis, we present evidence of a causal effect on osteoarthritis risk for variants associated with the expression of ten genes that have not been previously reported as effector genes in genome-wide association studies in osteoarthritis. Our findings point to key molecular pathways as drivers of cartilage degeneration and identify high-value drug targets and repurposing opportunities.

中文翻译：

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原代软骨转录特征反映了支撑骨关节炎的细胞类型特异性分子途径


由于我们在分子水平上对疾病过程的理解存在差距，骨关节炎的转化工作受到阻碍。在这里，我们提供了高病级和低病级软骨组织明显转录变化的证据，指出了参与疾病进展的胚胎过程。我们确定了骨关节炎软骨与人类胚胎和胎儿肢体细胞群之间的共享转录程序，指出肥厚前软骨细胞在低级别软骨中的转录程序增加，而高级疾病组织中成骨细胞特征的增加。我们发现骨关节炎遗传风险信号在 6 个基因共表达模块中富集，并表明这些转录特征反映了沿软骨内骨化发育轨迹的细胞类型特异性表达。使用这种网络方法与因果推理分析相结合，我们提供了与十个基因表达相关的变异对骨关节炎风险的因果影响的证据，这些基因以前在骨关节炎的全基因组关联研究中未作为效应基因报道。我们的研究结果指出关键分子途径是软骨退化的驱动因素，并确定了高价值的药物靶点和再利用机会。