Osteocytes, cells ensconced within mineralized bone matrix, are the primary skeletal mechanosensors. Osteocytes sense mechanical cues by changes in fluid flow shear stress (FFSS) across their dendritic projections. Loading-induced reductions of osteocytic Sclerostin (encoded by Sost) expression stimulates new bone formation. However, the molecular steps linking mechanotransduction and Sost suppression remain unknown. Here, we report that class IIa histone deacetylases (HDAC4 and HDAC5) are required for loading-induced Sost suppression and bone formation. FFSS signaling drives class IIa HDAC nuclear translocation through a signaling pathway involving direct HDAC5 tyrosine 642 phosphorylation by focal adhesion kinase (FAK), a HDAC5 post-translational modification that controls its subcellular localization. Osteocyte cell adhesion supports FAK tyrosine phosphorylation, and FFSS triggers FAK dephosphorylation. Pharmacologic FAK catalytic inhibition reduces Sost mRNA expression in vitro and in vivo. These studies demonstrate a role for HDAC5 as a transducer of matrix-derived cues to regulate cell type-specific gene expression.

骨细胞是矿化骨基质中的细胞，是主要的骨骼机械传感器。骨细胞通过其树突投射中流体流动剪切应力 (FFSS) 的变化来感知机械信号。负荷诱导的骨细胞硬化蛋白（由Sost编码）表达减少可刺激新骨形成。然而，连接机械传导和Sost抑制的分子步骤仍然未知。在这里，我们报告加载诱导的Sost需要 IIa 类组蛋白脱乙酰酶（HDAC4 和 HDAC5）抑制和骨形成。FFSS 信号通过涉及粘着斑激酶 (FAK) 的直接 HDAC5 酪氨酸 642 磷酸化的信号通路驱动 IIa 类 HDAC 核转位，FAK 是一种控制其亚细胞定位的 HDAC5 翻译后修饰。骨细胞粘附支持 FAK 酪氨酸磷酸化，而 FFSS 触发 FAK 去磷酸化。药理学 FAK 催化抑制可降低体外和体内的Sost mRNA 表达。这些研究证明了 HDAC5 作为基质衍生线索的转导器以调节细胞类型特异性基因表达的作用。