eIF2α signaling regulates autophagy of osteoblasts and the development of osteoclasts in OVX mice.,Cell Death & Disease

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eIF2α signaling regulates autophagy of osteoblasts and the development of osteoclasts in OVX mice.
Cell Death & Disease ( IF 8.1 ) Pub Date : 2019-12-04 , DOI: 10.1038/s41419-019-2159-z
Jie Li _{1,

2} , Xinle Li _{1,

2} , Daquan Liu _{1,

2} , Kazunori Hamamura ₃ , Qiaoqiao Wan ₃ , Sungsoo Na ₃ , Hiroki Yokota ₃ , Ping Zhang _{1,

2,

3,

4}

Affiliation

Bone loss in postmenopausal osteoporosis is induced chiefly by an imbalance of bone-forming osteoblasts and bone-resorbing osteoclasts. Salubrinal is a synthetic compound that inhibits de-phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α). Phosphorylation of eIF2α alleviates endoplasmic reticulum (ER) stress, which may activate autophagy. We hypothesized that eIF2α signaling regulates bone homeostasis by promoting autophagy in osteoblasts and inhibiting osteoclast development. To test the hypothesis, we employed salubrinal to elevate the phosphorylation of eIF2α in an ovariectomized (OVX) mouse model and cell cultures. In the OVX model, salubrinal prevented abnormal expansion of rough ER and decreased the number of acidic vesiculars. It regulated ER stress-associated signaling molecules such as Bip, p-eIF2α, ATF4 and CHOP, and promoted autophagy of osteoblasts via regulation of eIF2α, Atg7, LC3, and p62. Salubrinal markedly alleviated OVX-induced symptoms such as reduction of bone mineral density and bone volume fraction. In primary bone-marrow-derived cells, salubrinal increased the differentiation of osteoblasts, and decreased the formation of osteoclasts by inhibiting nuclear factor of activated T-cells cytoplasmic 1 (NFATc1). Live cell imaging and RNA interference demonstrated that suppression of osteoclastogenesis is in part mediated by Rac1 GTPase. Collectively, this study demonstrates that ER stress-autophagy axis plays an important role in OVX mice. Bone-forming osteoblasts are restored by maintaining phosphorylation of eIF2α, and bone-resorbing osteoclasts are regulated by inhibiting NFATc1 and Rac1 GTPase.

中文翻译：

eIF2α 信号传导调节 OVX 小鼠中成骨细胞的自噬和破骨细胞的发育。

绝经后骨质疏松症的骨丢失主要是由骨形成成骨细胞和骨吸收破骨细胞的不平衡引起的。 Salubrinal 是一种合成化合物，可抑制真核翻译起始因子 2 α (eIF2α) 的去磷酸化。 eIF2α 的磷酸化可减轻内质网 (ER) 应激，从而激活自噬。我们假设 eIF2α 信号通过促进成骨细胞自噬和抑制破骨细胞发育来调节骨稳态。为了验证这一假设，我们使用 salubrinal 来提高卵巢切除 (OVX) 小鼠模型和细胞培养物中 eIF2α 的磷酸化。在 OVX 模型中，salubrinal 可以防止粗糙 ER 的异常扩张并减少酸性囊泡的数量。它调节内质网应激相关信号分子，如 Bip、p-eIF2α、ATF4 和 CHOP，并通过调节 eIF2α、Atg7、LC3 和 p62 促进成骨细胞自噬。 Salubrinal 显着减轻了 OVX 引起的症状，例如骨密度和骨体积分数的降低。在原代骨髓源性细胞中，salubrinal 通过抑制活化 T 细胞胞浆核因子 1 (NFATc1) 增加成骨细胞的分化，并减少破骨细胞的形成。活细胞成像和 RNA 干扰表明，破骨细胞生成的抑制部分是由 Rac1 GTPase 介导的。总的来说，这项研究表明内质网应激-自噬轴在 OVX 小鼠中发挥着重要作用。成骨细胞通过维持 eIF2α 的磷酸化来恢复，骨吸收破骨细胞通过抑制 NFATc1 和 Rac1 GTPase 来调节。

更新日期：2019-12-05

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