Department of Pharmacology, Chonnam National University Medical School, Gwangju 61469, Republic of Korea.
Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju 61469, Republic of Korea; and.
J Immunol. 2018 Mar 1;200(5):1661-1670. doi: 10.4049/jimmunol.1701036. Epub 2018 Jan 29.
Endoplasmic reticulum (ER) stress is triggered by various metabolic factors, such as cholesterol and proinflammatory cytokines. Recent studies have revealed that ER stress is closely related to skeletal disorders, such as osteoporosis. However, the precise mechanism by which ER stress regulates osteoclast differentiation has not been elucidated. In this study, we identified an ER-bound transcription factor, cAMP response element-binding protein H (CREBH), as a downstream effector of ER stress during RANKL-induced osteoclast differentiation. RANKL induced mild ER stress and the simultaneous accumulation of active nuclear CREBH (CREBH-N) in the nucleus during osteoclastogenesis. Overexpression of CREBH-N in osteoclast precursors enhanced RANKL-induced osteoclast formation through NFATc1 upregulation. Inhibiting ER stress using a specific inhibitor attenuated the expression of osteoclast-related genes and CREBH activation. In addition, inhibition of reactive oxygen species using -acetylcysteine attenuated ER stress, expression of osteoclast-specific marker genes, and RANKL-induced CREBH activation. Furthermore, inhibition of ER stress and CREBH signaling pathways using an ER stress-specific inhibitor or CREBH small interfering RNAs prevented RANKL-induced bone destruction in vivo. Taken together, our results suggest that reactive oxygen species/ER stress signaling-dependent CREBH activation plays an important role in RANKL-induced osteoclastogenesis. Therefore, inactivation of ER stress and CREBH signaling pathways may represent a new treatment strategy for osteoporosis.
内质网（ER）应激是由各种代谢因子触发的，如胆固醇和促炎细胞因子。最近的研究表明，ER 应激与骨骼疾病密切相关，如骨质疏松症。然而，ER 应激调节破骨细胞分化的确切机制尚未阐明。在本研究中，我们确定了一种 ER 结合转录因子，cAMP 反应元件结合蛋白 H（CREBH），作为 RANKL 诱导的破骨细胞分化过程中 ER 应激的下游效应因子。RANKL 诱导轻度 ER 应激，并在破骨细胞发生过程中同时在核内积累活性核 CREBH（CREBH-N）。在破骨细胞前体中过表达 CREBH-N 通过上调 NFATc1 增强了 RANKL 诱导的破骨细胞形成。使用特异性抑制剂抑制 ER 应激可减弱破骨细胞相关基因的表达和 CREBH 激活。此外，使用 N-乙酰半胱氨酸抑制活性氧可减轻 ER 应激、破骨细胞特异性标记基因的表达和 RANKL 诱导的 CREBH 激活。此外，使用 ER 应激特异性抑制剂或 CREBH 小干扰 RNA 抑制 ER 应激和 CREBH 信号通路可防止 RANKL 诱导的体内骨破坏。总之，我们的研究结果表明，活性氧/ER 应激信号依赖性 CREBH 激活在 RANKL 诱导的破骨细胞发生中起重要作用。因此，抑制 ER 应激和 CREBH 信号通路可能是骨质疏松症的一种新的治疗策略。
