Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, 1011 N. University Ave., Ann Arbor, MI 48109-1078, USA.
J Bone Miner Res. 2012 Jun;27(6):1263-74. doi: 10.1002/jbmr.1574.
Bone can adapt its structure in response to mechanical stimuli. At the cellular level, this involves changes in chromatin organization, gene expression, and differentiation, but the underlying mechanisms are poorly understood. Here we report on the involvement of RUNX2, a bone-related transcription factor, in this process. Fluid flow shear stress loading of preosteoblasts stimulated translocation of extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) to the nucleus where it phosphorylated RUNX2 on the chromatin of target genes, and increased histone acetylation and gene expression. MAPK signaling and two RUNX2 phosphoacceptor sites, S301 and S319, were critical for this response. Similarly, in vivo loading of mouse ulnae dramatically increased ERK and RUNX2 phosphorylation as well as expression of osteoblast-related genes. These findings establish ERK/MAPK-mediated phosphorylation of RUNX2 as a critical step in the response of preosteoblasts to dynamic loading and define a novel mechanism to explain how mechanical signals induce gene expression in bone.
骨骼可以根据机械刺激来调整其结构。在细胞水平上，这涉及染色质组织、基因表达和分化的变化，但潜在的机制还知之甚少。在这里，我们报告了与骨相关的转录因子 RUNX2 在此过程中的参与。预先培养的成骨细胞在流体流动切应力的加载下，刺激细胞外信号调节激酶（ERK）/丝裂原激活蛋白激酶（MAPK）向细胞核易位，在那里它使靶基因的 RUNX2 染色质上的磷酸化，并增加组蛋白乙酰化和基因表达。MAPK 信号和两个 RUNX2 磷酸接受位点 S301 和 S319 对于这种反应至关重要。同样，对小鼠尺骨的体内加载极大地增加了 ERK 和 RUNX2 的磷酸化以及与成骨细胞相关的基因的表达。这些发现确立了 ERK/MAPK 介导的 RUNX2 磷酸化作为成骨细胞对动态加载反应的关键步骤，并定义了一种新的机制来解释机械信号如何诱导骨骼中的基因表达。
