SOX9 regulated matrix proteins are increased in patients serum and correlate with severity of liver fibrosis
SOX9 regulated matrix proteins are increased in patients serum and correlate with severity of liver fibrosis
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DOI：
10.1038/s41598-018-36037-4
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发表时间：
2018-12-17
影响因子：
4.6
通讯作者：
Hanley, Karen Piper
中科院分区：
文献类型：
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作者：
Athwal, Varinder S.;Pritchett, James;Hanley, Karen Piper
细胞外基质（ECM）沉积和由此产生的瘢痕在肝纤维化的发病机制和进展中起主要作用。确定ECM沉积的核心调节因子可能会导致迫切需要的疾病的诊断和治疗策略。转录因子性别决定区Y盒9（SOX 9）积极参与疤痕形成，其在肝纤维化患者中的流行率可预测进展。在这项研究中，Sox9废除的肌成纤维细胞的转录组学方法鉴定了>30%的由Sox9调节的基因与ECM相关。对这些数据的进一步审查鉴定了一组高度表达的ECM蛋白，包括骨桥蛋白（OPN）、骨激活素（GPNMB）、纤连蛋白（FN 1）、骨连接蛋白（OPN）和波形蛋白（Vim）作为适合于在患者血清中测定的SOX 9靶标。在体内，所有SOX调节的靶点在人类疾病和小鼠纤维化模型中增加，而在实质和胆道纤维化小鼠中Sox9丢失后减少。在患者血清样品中，SOX 9调节的ECM蛋白响应于纤维化严重程度而改变，而与已建立的临床生物标志物的比较表明OPN和Vim在检测早期纤维化方面具有优势。这些数据支持SOX 9在纤维化潜在机制中的作用，并强调SOX 9及其下游靶点是对肝纤维化患者进行分层的新措施。
Extracellular matrix (ECM) deposition and resultant scar play a major role in the pathogenesis and progression of liver fibrosis. Identifying core regulators of ECM deposition may lead to urgently needed diagnostic and therapetic strategies for the disease. The transcription factor Sex determining region Y box 9 (SOX9) is actively involved in scar formation and its prevalence in patients with liver fibrosis predicts progression. In this study, transcriptomic approaches of Sox9-abrogated myofibroblasts identified >30% of genes regulated by SOX9 relate to the ECM. Further scrutiny of these data identified a panel of highly expressed ECM proteins, including Osteopontin (OPN), Osteoactivin (GPNMB), Fibronectin (FN1), Osteonectin (SPARC) and Vimentin (VIM) as SOX9 targets amenable to assay in patient serum. In vivo all SOX-regulated targets were increased in human disease and mouse models of fibrosis and decreased following Sox9-loss in mice with parenchymal and biliary fibrosis. In patient serum samples, SOX9-regulated ECM proteins were altered in response to fibrosis severity, whereas comparison with established clinical biomarkers demonstrated superiority for OPN and VIM at detecting early stages of fibrosis. These data support SOX9 in the mechanisms underlying fibrosis and highlight SOX9 and its downstream targets as new measures to stratify patients with liver fibrosis.