Hedgehog signaling regulates osteoblast differentiation in zebrafish larvae through modulation of autophagy
Hedgehog signaling regulates osteoblast differentiation in zebrafish larvae through modulation of autophagy
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DOI：
10.1242/bio.040840
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发表时间：
2019-05-01
期刊：
影响因子：
2.4
通讯作者：
Zhao, Qiong
中科院分区：
文献类型：
--
作者：
Hu, Zhanying;Chen, Bo;Zhao, Qiong
成骨细胞分化受损可能导致骨代谢疾病，如骨质疏松症。最近的研究表明，hedgehog（Hh）信号和自噬是骨分化的两个重要调控因子。为了进一步剖析它们在骨发育中的关系，我们使用斑马鱼幼虫模型来研究这些信号之一的破坏如何影响另一个信号的功能并影响成骨细胞分化。我们的结果表明，Hh信号的激活对自噬产生负调节。然而，通过敲低atg5表达来抑制自噬并没有改变Hh信号传导，但显著上调了成骨细胞相关基因的表达，并增加了骨矿化，特别是在den区域。相反，通过环巴胺处理抑制Hh信号通路抑制成骨细胞相关基因的表达并降低骨矿化。与这些发现一致，通过敲低SHH和Gli2基因阻断Hh信号传导导致成骨细胞分化缺陷，而通过敲低Ptch 1促进Hh信号传导有利于成骨细胞分化。因此，我们的研究结果支持Hh信号通路的激活负调节自噬，从而促进成骨细胞分化。相反，诱导自噬抑制成骨细胞分化。我们的工作揭示了Hh信号通路调控骨发育的机制。
Impaired osteoblast differentiation may result in bone metabolic diseases such as osteoporosis. It was reported recently that hedgehog (Hh) signaling and autophagy are two important regulators of bone differentiation. In order to further dissect their relationship in bone development, we used a zebrafish larvae model to investigate how disruption of one of these signals affects the function of the other and impacts osteoblast differentiation. Our results showed that activation of Hh signaling negatively regulated autophagy. However, suppression of autophagy by knocking down atg5 expression did not alter Hh signaling, but dramatically upregulated the expression of osteoblast-related genes and increased bone mineralization, especially in the den region. On the contrary, inhibition of the Hh signaling pathway by cyclopamine treatment suppressed the expression of osteoblast-related genes and decreased bone mineralization. In agreement with these findings, blocking Hh signaling through knockdown SHH and Gli2 genes led to defective osteoblast differentiation, while promoting Hh signaling by knockdown Ptch1 was beneficial to osteoblast differentiation. Our results thus support that activation of the Hh signaling pathway negatively regulates autophagy and consequentially promotes osteoblast differentiation. On the contrary, induction of autophagy inhibits osteoblast differentiation. Our work reveals the mechanism underlying Hh signaling pathway regulation of bone development.