Organism scale mechanical forces elicit cellular scale changes through coordinated regulation of multiple signaling pathways. The mechanisms by which cells integrate signaling to generate a unified biological response remains a major question in mechanobiology. For example, the mechanosensitive response of bone and other tissues requires coordinated signaling by the transforming growth factor beta (TGFβ) and Wnt pathways through mechanisms that are not well-defined. Here we report a new microRNA-dependent mechanism that mediates mechanosensitive crosstalk between TGFβ and Wnt signaling in osteocytes exposed to fluid shear stress (FSS). From 60 mechanosensitive microRNA (miRs) identified by small-RNAseq, miR100 expression is suppressed by in vivo hindlimb loading in the murine tibia and by cellular scale FSS in OCY454 cells. Though FSS activates both TGFβ and Wnt signaling in osteocytes, only TGFβ represses miR-100 expression. miR-100, in turn, antagonizes Wnt signaling by targeting and inhibiting expression of Frizzled receptors (FZD5/FZD8). Accordingly, miR-100 inhibition blunts FSS- and TGFβ-inducible Wnt signaling. Therefore, our results identify FSS-responsive miRNAs in osteocytes, including one that integrates the mechanosensitive function of two essential signaling pathways in the osteoanabolic response of bone to mechanical load.

中文翻译：

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机械敏感性 miR-100 在流体剪切应力期间协调骨细胞中的 TGFβ 和 Wnt 信号传导

生物体尺度机械力通过多种信号通路的协调调节引起细胞尺度变化。细胞整合信号以产生统一的生物反应的机制仍然是机械生物学的一个主要问题。例如，骨骼和其他组织的机械敏感反应需要转化生长因子 β (TGFβ) 和 Wnt 通路通过尚未明确定义的机制进行协调的信号传导。在这里，我们报告了一种新的 microRNA 依赖性机制，该机制介导暴露于流体剪切应力 (FSS) 的骨细胞中 TGFβ 和 Wnt 信号传导之间的机械敏感串扰。从通过 small-RNAseq 鉴定的 60 个机械敏感 microRNA (miR) 中，miR100 的表达受到小鼠胫骨中的体内后肢负荷和 OCY454 细胞中的细胞规模 FSS 的抑制。虽然 FSS 激活骨细胞中的 TGFβ 和 Wnt 信号传导，但只有 TGFβ 抑制 miR-100 的表达。反过来，miR-100 通过靶向和抑制卷曲受体 (FZD5/FZD8) 的表达来拮抗 Wnt 信号传导。因此，miR-100 抑制减弱了 FSS 和 TGFβ 诱导的 Wnt 信号传导。因此，我们的结果确定了骨细胞中的 FSS 反应性 miRNA，包括一种在骨对机械负荷的骨合成代谢反应中整合了两种基本信号通路的机械敏感功能的 miRNA。