Kruppel-Like Factor 4 represses osteoblast differentiation via ciliary Hedgehog signaling
Kruppel-Like Factor 4 represses osteoblast differentiation via ciliary Hedgehog signaling
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Kruppel 样因子 4 通过睫状 Hedgehog 信号传导抑制成骨细胞分化
DOI：
10.1016/j.yexcr.2018.09.002
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Takeuchi et al.
中科院分区：
文献类型：
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作者：
Kurz;W.;Micheuz;P.;Christeson;G. L.;Reagan;M. K.;Shervais;J. W.;Kutterolf;S.;Robertson;A.;Krenn;K.;Michibayashi;K.;Quandt;D.;Takeuchi et al.
初级纤毛是在大多数类型的细胞中观察到的附属物，并且用作感知环境信号的细胞天线。越来越多的证据表明，正确的纤毛发生和纤毛功能是不可或缺的正常骨骼发育，调节信号通路的骨发育的重要。然而，成骨细胞中的纤毛发生是否受到骨相关因子的调节在很大程度上尚不清楚。在这里，我们表明，Kruppel样因子4（KLF4），这是已知的抑制成骨细胞分化，支持纤毛在培养的成骨细胞的形成和维护，然而，在KLF4诱导的细胞中观察到的纤毛的长度显着较短的控制细胞相比。基础Hedgehog信号被KLF4抑制。值得注意的是，使用Smoothened激动剂激活Hedgehog信号传导显著挽救了成骨细胞矿化和成骨细胞基因表达。全球基因表达分析表明，KLF4诱导的基因，包括核受体，孕烷X受体（PXR），和PXR抑制颅骨成骨细胞矿化和抑制Gli1的表达类似的效果，通过诱导KLF4。我们的研究结果表明，KLF4通过抑制Hedgehog信号的基础激活，在维持成骨细胞处于未成熟状态中起重要作用。
Primary cilia are appendages observed in most types of cells, and serve as cellular antennae for sensing environmental signals. Evidence is accumulating that correct ciliogenesis and ciliary functions are indispensable for normal skeletal development by regulating signaling pathways important for bone development. However, whether ciliogenesis is regulated by bone-related factors in osteoblasts is largely unknown. Here we show that Kruppel-Like Factor 4 (KLF4), which is known to repress osteoblast differentiation, supports the formation and maintenance of cilia in cultured osteoblasts; however, the length of the cilia observed in KLF4-induced cells were significantly shorter compared to the control cells. Basal Hedgehog signaling was repressed by KLF4. Significantly, activating Hedgehog signaling using a Smoothened agonist significantly rescued osteoblast mineralization and osteoblastic gene expressions. Global gene expression analysis showed that KLF4 induced number of genes including the nuclear receptor, Pregnane X receptor (PXR), and PXR repressed calvarial osteoblast mineralization and repressed Gli1 expression similar as the effect observed by inducing KLF4. Our results implicate that KLF4 plays important roles for maintaining osteoblasts in an immature state by repressing basal activation of the Hedgehog signaling.