CRLF1 Is a Key Regulator in the Ligamentum Flavum Hypertrophy.
CRLF1 Is a Key Regulator in the Ligamentum Flavum Hypertrophy.
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CRLF1 是黄韧带肥大的关键调节因子
DOI：
10.3389/fcell.2020.00858
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发表时间：
2020
影响因子：
5.5
通讯作者：
Wang L
中科院分区：
文献类型：
--
作者：
Zheng Z;Ao X;Li P;Lian Z;Jiang T;Zhang Z;Wang L
黄韧带肥厚（HLF）是腰椎管狭窄症（LSS）的常见原因之一。HLF的关键分子和机制尚不清楚。在这里，我们使用了一个整合的转录组和蛋白质组学分析的人黄韧带（LF），随后的免疫组织化学和实时PCR检测，显示上调CRLF 1是HLF的主要反应。TGF-β1通过SMAD 3途径促进CRLF 1 mRNA表达。CRLF 1通过ERK信号通路在转录后水平增强LF纤维化，并且是TGF-β1的促纤维化作用所必需的。研究表明，CRLF 1的敲除可以减少炎症细胞因子和机械应力引起的纤维化。此外，我们发现双足站立姿势可以引起HLF和CRLF 1表达上调小鼠LF。CRLF 1的过表达被指示在体内引起HLF，而CRLF 1敲低阻碍了双足站立小鼠中HLF的形成。这些结果揭示了CRLF 1在LF肥大中的关键作用。我们认为抑制CRLF 1是治疗HLF的一种潜在的治疗策略。
Hypertrophy of the ligamentum flavum (HLF) is one of the common causes of lumbar spinal stenosis (LSS). The key molecules and mechanisms responsible for HLF remain unclear. Here, we used an integrated transcriptome and proteomics analysis of human ligamentum flavum (LF), and subsequent immunohistochemistry and real-time PCR assays, to show upregulation of CRLF1 to be the dominant response to HLF. TGF-β1 significantly increased mRNA expression of CRLF1 through SMAD3 pathway. CRLF1 enhanced LF fibrosis via ERK signaling pathway at the post-transcriptional level and was required for the pro-fibrotic effect of TGF-β1. Knockdown of CRLF1 was shown here to reduce fibrosis caused by inflammatory cytokines and mechanical stress. Furthermore, we found that bipedal standing posture can cause HLF and upregulation of CRLF1 expression in mice LF. Overexpression of CRLF1 was indicated to cause HLF in vivo, whereas CRLF1 knockdown impeded the formation of HLF in bipedal standing mice. These results revealed a crucial role of CRLF1 in LF hypertrophy. We propose that inhibition of CRLF1 is a potential therapeutic strategy to treat HLF.