Mechanical responses and signal transduction pathways in stretched osteocytes
Mechanical responses and signal transduction pathways in stretched osteocytes
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DOI：
10.1007/s007740050065
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发表时间：
1999-01-01
影响因子：
3.3
通讯作者：
Mikuni-Takagaki, Y
中科院分区：
文献类型：
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作者：
Mikuni-Takagaki, Y
骨中的机械传导本质上是复杂的，受到许多调节剂如PTH、前列腺素和细胞外Ca 2+的影响。据推测，骨细胞，骨骼中的树突状驻留细胞，传递机械负荷的信号，导致合成代谢反应，如c-Sos，胰岛素样生长因子-I（IGF-I）和骨钙素的表达。然而，到目前为止，无论是骨细胞反应的实际刺激还是信号转导途径都没有很好的理解。培养的原代大鼠骨细胞表现出不同的反应，拉伸取决于其发育阶段：年轻的骨细胞，逐渐成为树突状显示惊人的反应，应变在生理水平，这些包括早期反应的cAMP分泌和晚期反应，如生产IGF-I和骨钙素蛋白。其mRNA的稳态水平的上调是双相的，在PGHS-2（诱导性前列腺素G/H合酶;考克斯-2）基因表达的两个峰值之前。与c-fos典型的瞬时即刻早期表达相比，PGHS-2在牵张开始后约8h显示另一个明显的峰。IGF-I和骨钙素表达的第二个峰完全依赖于PGHS-2表达的第一个波，从NS 398的抑制判断。PGHS-2可能在骨“记忆效应”对成骨机械刺激的延长的合成代谢反应中起关键作用。在这些细胞中，细胞外Ca 2+是它们对拉伸的反应所必需的。此外，牵张激活通道的阻断剂钆（Gd 3+）和上皮样Na通道的阻断剂苯扎明（benzamil）联合使用可消除牵张的影响，如骨钙素表达升高。虽然电压操作或钙激活的钙通道或Na+驱动机制，如钠钙交换，例如，是功能，次级钙进入途径的细节是不确定的。然而，可以想象的是，钙流入，无论是原发性的还是继发性的，都通过骨细胞中的Ser/Thr激酶信号通路触发骨对拉伸的合成代谢反应。
Mechanotransduction in bone is complex in nature, being influenced by many modulators such as PTH, prostanoids, and extracellular Ca2+. It has been postulated that osteocytes, dendritic resident cells in bone, transduce signals of mechanical loading that result in anabolic responses such as the expression of c-Sos, insulin-like growth factor-I (IGF-I), and osteocalcin. To date, however, neither the actual stimuli to which osteocytes respond nor the pathways of signal transduction are well understood. Cultured primary rat bone cells exhibit distinct responses to stretching depending on their developmental stages: young osteocytes that become progressively dendritic show striking responses to strain at physiological levels; these include an early response of cAMP secretion and the late responses such as the production of IGF-I and osteocalcin proteins. The upregulation of steady state levels of their mRNA is biphasic, being preceded by two peaks of PGHS-2 (inducive prostaglandin G/H synthase; cox-2) gene expression. Compared to a typical transient immediate early expression of c-fos, PGHS-2 shows another distinct peak about 8 h after the initiation of stretching. Second peaks in IGF-I and osteocalcin expression are entirely dependent on the first wave of PGHS-2 expression judging from the inhibition by NS398. PGHS-2 is perhaps critically involved in the prolonged anabolic responses of bone "memory effect" to the osteogenic mechanical stimulation. In these cells, the extracellular Ca2+ is essential to their response to stretching. Furthermore, the blockers of stretch-activated channels, gadolinium (Gd3+), and of epithelial-like Na channels, benzamil, in combination abolish the effects of stretching such as elevated osteocalcin expression. Although voltage-operated or calcium-activated calcium channels or Na+-driven mechanisms, such as a Na-Ca exchanger, for example, are functioning, particulars of secondary Ca entry pathways are not certain at this point. It is conceivable, however, that the calcium influxes, both primary and secondary, trigger the anabolic reaction of bone to stretching via Ser/Thr kinase signaling pathways in osteocytic cells.