Regulation of synthesis of osteoprotegerin and soluble receptor activator of nuclear factor-κB ligand in normal human osteoblasts via the p38 mitogen-activated protein kinase pathway by the application of cyclic tensile strain
Regulation of synthesis of osteoprotegerin and soluble receptor activator of nuclear factor-κB ligand in normal human osteoblasts via the p38 mitogen-activated protein kinase pathway by the application of cyclic tensile strain
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DOI：
10.1007/s00774-005-0615-6
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发表时间：
2005-09-01
影响因子：
3.3
通讯作者：
Kimura, H
中科院分区：
文献类型：
--
作者：
Kusumi, A;Sakaki, H;Kimura, H
机械应力被认为在骨重塑中发挥重要作用。然而，人们对机械应力和骨重塑之间的相关性知之甚少。在这种情况下，使用针对人成骨细胞的循环拉伸应变（CTS）模型，检查了骨保护素（OPG）和核因子κB配体可溶性受体激活剂（sRANKL）的合成以及丝裂原激活蛋白激酶（MAPK）的激活。连续3天每天一次、每次4小时、7%、0.25-Hz CTS的应用同时引起成骨细胞中OPG合成的增加和sRANKL释放和RANKL mRNA表达的减少。至于应用CTS对成骨细胞中MAPK的激活，应用CTS后10-20分钟p38 MAPK被激活，但细胞外信号调节激酶（ERK1/2）和c-Jun NH2末端激酶（JNK）没有被这样的应用激活。此外，当CTS每天一次持续4小时连续1、2或3天应用于成骨细胞时，p38 MAPK活化在3天期间得以维持，但同时ERK1/2活化逐日下调。然后，当连续 3 天每天一次、每次 4 小时将 CTS 应用于用 p38 MAPK 抑制剂 SB203580 预处理 1 小时的成骨细胞时，OPG 合成受到剂量依赖性抑制，并且对 sRANKL 释放和 RANKL mRNA 表达的抑制被消除。这些结果表明，成骨细胞中 OPG 和 sRANKL 合成对 CTS 应用的生物反应是通过 p38 MAPK 途径调节的，表明 CTS 可能调节和调节骨代谢。
Mechanical stress is thought to play an important role in bone remodeling. However, the correlation between mechanical stress and bone remodeling is poorly understood. In this context, using a model of cyclic tensile strain (CTS) toward human osteoblasts, synthesis of osteoprotegerin (OPG) and soluble receptor activator of nuclear factor-kappa B ligand (sRANKL), and the activation of mitogen-activated protein kinases (MAPKs) were examined. The application of 7%, 0.25-Hz CTS once a day for 4 h for 3 successive days simultaneously caused an increase of OPG synthesis and a decrease of sRANKL release and RANKL mRNA expression in osteoblasts. As for MAPKs activation in osteoblasts with the application of CTS, p38 MAPK was activated 10-20 min after the application of CTS, but extracellular signal-regulated kinase (ERK1/2) and c-Jun NH2-terminal kinase (JNK) were not activated by such application. Furthermore, when CTS was applied once a day for 4 h for 1, 2, or 3 successive days to osteoblasts, p38 MAPK activation was maintained during the 3-day period but ERK1/2 activation was downregulated from day to day, simultaneously. Then, when CTS was applied once a day for 4 h for 3 successive days to osteoblasts pretreated with the p38 MAPK inhibitor SB203580 for 1 h, OPG synthesis was dose-dependently suppressed and inhibition of sRANKL release and RANKL mRNA expression was abrogated. These results indicate that biological responses of OPG and sRANKL synthesis in osteoblasts to the application of CTS are regulated via the p38 MAPK pathway and suggest that CTS might modulate and regulate bone metabolism.