A positive loop formed by SOX11 and periostin upregulates TGF-β signals leading to skin fibrosis
A positive loop formed by SOX11 and periostin upregulates TGF-β signals leading to skin fibrosis
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SOX11 和骨膜素形成的正环上调 TGF-β 信号，导致皮肤纤维化
DOI：
10.1016/j.jid.2022.12.008
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发表时间：
2022
影响因子：
6.5
通讯作者：
Izuhara Kenji
中科院分区：
文献类型：
--
作者：
Nanri Yasuhiro;Nunomura Satoshi;Honda Yuko;Takedomi Hironobu;Yamaguchi Yukie;Izuhara Kenji
系统性硬化症(SSC)是一种以器官纤维化、血管损伤和自身免疫为特征的慢性、异质性结缔组织疾病。转化生长因子-β在包括SSc在内的肝纤维化的发生中起核心作用。Periostin是一种基质细胞蛋白，通过放大转化生长因子-β信号在纤维化的发生中发挥关键作用。Sox11是一种转录因子，在胚胎器官发育过程中发挥着重要作用。我们之前已经证明了sox11诱导Periostin的表达。然而，转化生长因子-β信号、Periostin和Sox11之间的相互作用在SSc发病机制中的作用尚不清楚。在本研究中，我们发现大多数自发性硬皮病患者的真皮成纤维细胞克隆都表现出结构性的高表达SOX11，这是由转化生长因子-β1显著诱导的。SOX11与Periostin形成正环，激活真皮成纤维细胞中转化生长因子-β信号。表达Postn的成纤维细胞Sox11in基因缺失对博莱霉素致真皮纤维化的影响此外，利用基因芯片技术，我们在SSc真皮成纤维细胞中鉴定了几种依赖于转化生长因子-β/Sox11/Periostin通路的纤维化因子。总而言之，我们的发现表明，在成纤维细胞中，Sox11和Periostin形成的正环上调了转化生长因子-β信号，导致皮肤纤维化。
Systemic sclerosis (SSc) is a chronic, heterogeneous disease of connective tissue characterized by organ fibrosis together with vascular injury and autoimmunity. TGF-β plays a central role in generating fibrosis, including SSc. Periostin is a matricellular protein playing a key role in the generation of fibrosis by amplifying the TGF-β signals. SOX11 is a transcription factor playing several important roles in organ development in embryos. We have previously shown that SOX11 induces periostin expression. However, the roles of the interactions among the TGF-β signals, periostin, and SOX11 remain unknown in the pathogenesis of SSc. In this study, we found that most clones of dermal fibroblasts derived from patients with SSc showed constitutive, high expression of SOX11, which is significantly induced by TGF-β1. SOX11 forms a positive loop with periostin to activate the TGF-β signals in SSc dermal fibroblasts. Genetic deletion ofSox11inPostn-expressing fibroblasts impairs dermal fibrosis by bleomycin. Moreover, using the DNA microarray method, we identified several fibrotic factors dependent on the TGF-β/SOX11/periostin pathway in SSc dermal fibroblasts. Our findings, taken together, show that a positive loop formed by SOX11 and periostin in fibroblasts upregulates the TGF-β signals, leading to skin fibrosis.