Canonical and noncanonical TGF-β signaling regulate fibrous tissue differentiation in the axial skeleton.
Canonical and noncanonical TGF-β signaling regulate fibrous tissue differentiation in the axial skeleton.
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DOI：
10.1038/s41598-020-78206-4
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发表时间：
2020-12-07
影响因子：
4.6
通讯作者：
Serra R
中科院分区：
文献类型：
--
作者：
Clayton SW;Ban GI;Liu C;Serra R
以前，我们发现胚胎小鼠巩膜中TGF-β 2型受体的缺失导致脊柱纤维结缔组织的缺陷。在这里，我们研究了TGF-β如何调节纤维标记物：硬化蛋白、纤维调节蛋白和Adamts 12的表达。我们发现，TGF-β刺激巩膜轴mRNA的表达2小时和纤维调节蛋白和Adamts 12 mRNA的8小时的处理。TGF-β对巩膜轴的调节不需要新的蛋白质合成;然而，纤维调节蛋白和Adamts 12的表达需要蛋白质合成，表明中间体的必要性。我们随后证明Scleraxis是TGF-β调节纤维调节蛋白和Adamtsl 2表达的潜在中间体。经典效应子Smad 3对于TGF-β介导的巩膜轴调节不是必需的。Smad 3是调节纤维调节蛋白和Adamts 12所必需的，但不足以用TGF-β处理来超诱导表达。接下来，测试了几种非经典TGF-β途径的作用。我们发现ERK 1/2被TGF-β激活，并且需要调节硬化素、纤维调节蛋白和Adamts 1/2的表达。基于这些结果，我们提出了一个模型，其中TGF-β通过ERK 1/2调节Scleraxis，然后Scleraxis和Smad 3协同调节Fibromodulin和Adamts 1/2。这些结果为TGFβ介导的纤维分化提供了一种新的信号机制。
Previously, we showed that embryonic deletion of TGF-β type 2 receptor in mouse sclerotome resulted in defects in fibrous connective tissues in the spine. Here we investigated how TGF-β regulates expression of fibrous markers: Scleraxis, Fibromodulin and Adamtsl2. We showed that TGF-β stimulated expression of Scleraxis mRNA by 2 h and Fibromodulin and Adamtsl2 mRNAs by 8 h of treatment. Regulation of Scleraxis by TGF-β did not require new protein synthesis; however, protein synthesis was required for expression of Fibromodulin and Adamtsl2 indicating the necessity of an intermediate. We subsequently showed Scleraxis was a potential intermediate for TGF-β-regulated expression of Fibromodulin and Adamtsl2. The canonical effector Smad3 was not necessary for TGF-β-mediated regulation of Scleraxis. Smad3 was necessary for regulation of Fibromodulin and Adamtsl2, but not sufficient to super-induce expression with TGF-β treatment. Next, the role of several noncanonical TGF-β pathways were tested. We found that ERK1/2 was activated by TGF-β and required to regulate expression of Scleraxis, Fibromodulin, and Adamtsl2. Based on these results, we propose a model in which TGF-β regulates Scleraxis via ERK1/2 and then Scleraxis and Smad3 cooperate to regulate Fibromodulin and Adamtsl2. These results define a novel signaling mechanism for TGFβ-mediated fibrous differentiation in sclerotome.
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