Abstract：
Transposable elements (TEs) are mobile genetic modules of viral derivation that have been co-opted to become modulators of mammalian gene expression. TEs are a major source of endogenous dsRNAs, signaling molecules able to coordinate inflammatory responses in various physiological processes. Here, we provide evidence for a positive involvement of TEs in inflammation-driven bone repair and mineralization. In newly fractured mice bone, we observed an early transient upregulation of repeats occurring concurrently with the initiation of the inflammatory stage. In human bone biopsies, analysis revealed a significant correlation between repeats expression, mechanical stress and bone mineral density. We investigated a potential link between LINE-1 (L1) expression and bone mineralization by delivering a synthetic L1 RNA to osteoporotic patient-derived mesenchymal stem cells and observed a dsRNA-triggered protein kinase (PKR)-mediated stress response that led to strongly increased mineralization. This response was associated with a strong and transient inflammation, accompanied by a global translation attenuation induced by eIF2α phosphorylation. We demonstrated that L1 transfection reshaped the secretory profile of osteoblasts, triggering a paracrine activity that stimulated the mineralization of recipient cells.
摘要：
转座因子（TE）是病毒衍生的可移动遗传模块，已被选择成为哺乳动物基因表达的调节剂。TEs是内源性dsRNAs的主要来源，信号分子能够协调各种生理过程中的炎症反应。这里,我们提供了TEs积极参与炎症驱动的骨修复和矿化的证据.在新骨折的老鼠骨头中，我们观察到与炎症阶段开始同时发生的重复序列的早期短暂上调.在人体骨活检中，分析显示重复表达之间存在显著相关性，机械应力和骨密度。我们通过将合成的L1RNA递送至骨质疏松患者来源的间充质干细胞，研究了LINE-1（L1）表达与骨矿化之间的潜在联系，并观察到dsRNA触发的蛋白激酶（PKR）介导的应激反应，导致强烈增加的矿化。这种反应与强烈和短暂的炎症有关，伴随着由eIF2α磷酸化诱导的整体翻译衰减。我们证明了L1转染重塑了成骨细胞的分泌谱，触发刺激受体细胞矿化的旁分泌活动。
