Department of Molecular Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Japan.
Bone. 2013 May;54(1):172-8. doi: 10.1016/j.bone.2013.01.001. Epub 2013 Jan 11.
Mechanical stress is known to alter bone mass and the loss of force stimuli leads to reduction of bone mass. However, molecules involved in this phenomenon are incompletely understood. As mechanical force would affect signaling events in cells, we focused on a calcium channel, TRPV4 regarding its role in the effects of force stimuli on calcium in osteoblasts. TRPV4 expression levels were enhanced upon differentiation of osteoblasts in culture. We found that BMP-2 treatment enhanced TRPV4 gene expression in a dose dependent manner. BMP-2 effects on TRPV4 expression were suppressed by inhibitors for transcription and new protein synthesis. In these osteoblasts, a TRPV4-selective agonist, 4α-PDD, enhanced calcium signaling and the effects of 4α-PDD were enhanced in differentiated osteoblasts compared to the control cells. Fluid flow, as a mechanical stimulation, induced intracellular calcium oscillation in wild type osteoblasts. In contrast, TRPV4 deficiency suppressed calcium oscillation significantly even when the cells were subjected to fluid flow. These data suggest that TRPV4 is involved in the flow-induced calcium signaling in osteoblasts.
机械应力已知会改变骨量，而力刺激的丧失会导致骨量减少。然而，参与这一现象的分子尚不完全清楚。由于机械力会影响细胞中的信号事件，我们专注于钙通道 TRPV4，研究其在力刺激对成骨细胞中钙的影响中的作用。在培养中的成骨细胞分化过程中，TRPV4 的表达水平增强。我们发现 BMP-2 处理以剂量依赖的方式增强 TRPV4 基因表达。转录和新蛋白质合成抑制剂抑制了 BMP-2 对 TRPV4 表达的影响。在这些成骨细胞中，TRPV4 选择性激动剂 4α-PDD 增强了钙信号，并且与对照细胞相比，4α-PDD 的作用在分化的成骨细胞中增强。作为机械刺激的流体流动诱导野生型成骨细胞内的钙振荡。相比之下，即使细胞受到流体流动的影响，TRPV4 缺失也会显著抑制钙振荡。这些数据表明 TRPV4 参与了成骨细胞中流动诱导的钙信号。
