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.

中文翻译：

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LINE-1 RNA 通过 PKR 介导的炎症反应触发骨细胞中基质的形成。


转座因子 （TE） 是病毒衍生的移动遗传模块，已被选为哺乳动物基因表达的调节剂。TE 是内源性 dsRNA 的主要来源，内源性 dsRNA 是能够在各种生理过程中协调炎症反应的信号分子。在这里，我们提供了 TE 积极参与炎症驱动的骨骼修复和矿化的证据。在新骨折的小鼠骨骼中，我们观察到重复序列的早期瞬时上调与炎症阶段的开始同时发生。在人骨活检中，分析显示重复表达、机械应力和骨矿物质密度之间存在显着相关性。我们通过将合成的 L1 RNA 递送到骨质疏松患者来源的间充质干细胞来研究 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矿化强烈增加。这种反应与强烈的短暂炎症有关，并伴有 eIF2α 磷酸化诱导的整体翻译衰减。我们证明 L1 转染重塑了成骨细胞的分泌谱，触发了刺激受体细胞矿化的旁分泌活性。