LINE-1 RNA triggers matrix formation in bone cells via a PKR-mediated inflammatory response.

IF 9.4 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY EMBO Journal Pub Date : 2024-09-01 Epub Date: 2024-07-01 DOI:10.1038/s44318-024-00143-z
Arianna Mangiavacchi, Gabriele Morelli, Sjur Reppe, Alfonso Saera-Vila, Peng Liu, Benjamin Eggerschwiler, Huoming Zhang, Dalila Bensaddek, Elisa A Casanova, Carolina Medina Gomez, Vid Prijatelj, Francesco Della Valle, Nazerke Atinbayeva, Juan Carlos Izpisua Belmonte, Fernando Rivadeneira, Paolo Cinelli, Kaare Morten Gautvik, Valerio Orlando
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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.

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LINE-1 RNA 通过 PKR 介导的炎症反应引发骨细胞中基质的形成。
可转座元件(Transposable elements,TEs)是由病毒衍生而来的移动遗传模块,已成为哺乳动物基因表达的调节器。可转座元件是内源性 dsRNA 的主要来源,而 dsRNA 是一种信号分子,能够在各种生理过程中协调炎症反应。在这里,我们提供了 TEs 积极参与炎症驱动的骨修复和矿化的证据。在新骨折的小鼠骨骼中,我们观察到重复序列的早期短暂上调与炎症阶段的启动同时发生。在人体骨活检组织中,分析显示重复序列表达、机械应力和骨矿物质密度之间存在显著相关性。我们通过向骨质疏松症患者间充质干细胞递送合成的 L1 RNA,研究了 LINE-1(L1)表达与骨矿化之间的潜在联系。这种反应与强烈而短暂的炎症有关,并伴随着由eIF2α磷酸化诱导的全局翻译衰减。我们证明,L1转染重塑了成骨细胞的分泌谱,引发了一种旁分泌活动,刺激了受体细胞的矿化。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
EMBO Journal
EMBO Journal 生物-生化与分子生物学
CiteScore
18.90
自引率
0.90%
发文量
246
审稿时长
1.5 months
期刊介绍: The EMBO Journal has stood as EMBO's flagship publication since its inception in 1982. Renowned for its international reputation in quality and originality, the journal spans all facets of molecular biology. It serves as a platform for papers elucidating original research of broad general interest in molecular and cell biology, with a distinct focus on molecular mechanisms and physiological relevance. With a commitment to promoting articles reporting novel findings of broad biological significance, The EMBO Journal stands as a key contributor to advancing the field of molecular biology.
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