Compressive Force-Produced CCN2 Induces Osteocyte Apoptosis Through ERK1/2 Pathway
Compressive Force-Produced CCN2 Induces Osteocyte Apoptosis Through ERK1/2 Pathway
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DOI：
10.1002/jbmr.2115
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发表时间：
2014-05-01
影响因子：
6.2
通讯作者：
Takano-Yamamoto, Teruko
中科院分区：
文献类型：
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作者：
Hoshi, Kenji;Kawaki, Harumi;Takano-Yamamoto, Teruko
骨细胞产生多种因子，介导骨形成和骨吸收的发生，并在维持骨的动态平衡和对机械刺激的重塑中发挥作用。CCN2被认为在骨细胞对机械刺激的反应中发挥重要作用，但它在骨细胞中的作用尚不清楚。在这里，我们证明了CCN2在压力负荷下诱导骨细胞凋亡。压力增加了CCN2基因的表达和产量，诱导了骨细胞的凋亡。外源CCN2蛋白诱导细胞凋亡，中和抗体阻断负载诱导的细胞凋亡。我们进一步研究了CCN2是如何诱导负载的骨细胞凋亡的。在加载的骨细胞中，细胞外信号调节激酶1/2(ERK1/2)被激活，ERK1/2抑制剂阻断加载诱导的细胞凋亡。此外，外源CCN2蛋白可引起ERK1/2激活，而中和CCN2抗体可抑制负载诱导的ERK1/2激活。因此，本研究首次证实了在压力负荷作用下，骨细胞中CCN2的增加通过激活ERK1/2通路诱导细胞凋亡。(C)2014年美国骨与矿物研究学会。
Osteocytes produce various factors that mediate the onset of bone formation and resorption and play roles in maintaining bone homeostasis and remodeling in response to mechanical stimuli. One such factor, CCN2, is thought to play a significant role in osteocyte responses to mechanical stimuli, but its function in osteocytes is not well understood. Here, we showed that CCN2 induces apoptosis in osteocytes under compressive force loading. Compressive force increased CCN2 gene expression and production, and induced apoptosis in osteocytes. Application of exogenous CCN2 protein induced apoptosis, and a neutralizing CCN2 antibody blocked loading-induced apoptosis. We further examined how CCN2 induces loaded osteocyte apoptosis. In loaded osteocytes, extracellular signal-regulated kinase 1/2 (ERK1/2) was activated, and an ERK1/2 inhibitor blocked loading-induced apoptosis. Furthermore, application of exogenous CCN2 protein caused ERK1/2 activation, and the neutralizing CCN2 antibody inhibited loading-induced ERK1/2 activation. Therefore, this study demonstrated for the first time to our knowledge that enhanced production of CCN2 in osteocytes under compressive force loading induces apoptosis through activation of ERK1/2 pathway. (c) 2014 American Society for Bone and Mineral Research.