Hoshi Kenji, Kawaki Harumi, Takahashi Ichiro, Takeshita Nobuo, Seiryu Masahiro, Murshid Sakhr A, Masuda Taisuke, Anada Takahisa, Kato Ryushi, Kitaura Hideki, Suzuki Osamu, Takano-Yamamoto Teruko
Division of Orthodontics and Dentofacial Orthopedics, Tohoku University Graduate School of Dentistry, Sendai, Japan.
J Bone Miner Res. 2014;29(5):1244-57. doi: 10.1002/jbmr.2115.
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.
骨细胞产生多种介导骨形成和吸收起始的因子，并在响应机械刺激时维持骨稳态和重塑过程中发挥作用。其中一种因子CCN2，被认为在骨细胞对机械刺激的反应中起重要作用，但其在骨细胞中的功能尚未完全了解。在此，我们表明CCN2在压缩力加载下诱导骨细胞凋亡。压缩力增加了CCN2基因表达和产生，并诱导骨细胞凋亡。外源性CCN2蛋白的应用诱导了凋亡，而中和性CCN2抗体阻断了加载诱导的凋亡。我们进一步研究了CCN2如何诱导加载的骨细胞凋亡。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抑制剂阻断了加载诱导的凋亡。此外，外源性CCN2蛋白的应用导致ERK1/2激活，而中和性CCN2抗体抑制了加载诱导的ERK1/2激活。因此，据我们所知，本研究首次证明在压缩力加载下骨细胞中CCN2产生的增加通过ERK1/2途径的激活诱导凋亡。
