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

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 humans, 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, leading to dramatically increased mineralization. This response was associated with a strong, transient, inflammatory induction, accompanied by a global translation attenuation induced by eif2a phosphorylation. We demonstrated that L1 transfection reshaped the secretory profile of osteoblasts, triggering a paracrine activity that stimulated the mineralization of recipient cells.

INSTRUMENT(S): timsTOF Pro 2

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Mesenchymal Stem Cell

SUBMITTER: Dalila Bensaddek  

LAB HEAD: Valerio Orlando

PROVIDER: PXD051195 | Pride | 2024-10-17

REPOSITORIES: Pride