SdRNA-D43 Derived from Small Nucleolar RNA SnoRD43 Improves Chondrocyte Senescence and Osteoarthritis Progression by Negatively Regulating PINK1/Parkin-mediated Mitophagy Pathway Via Dual-targeting NRF1 and WIPI2

Overview

Journal Cell Commun Signal

Publisher Biomed Central

Specialties Biochemistry
Cell Biology

Date 2025 Feb 11

PMID 39934774

Authors

Zengfa Deng

Changzhao Li

Shu Hu

Yanlin Zhong

Wei Li

Zhencan Lin

Xiaolin Mo

Ming Li

Dongliang Xu

Dianbo Long

Guping Mao

Yan Kang

Affiliations

Soon will be listed here.

Abstract

Background: Chondrocyte senescence play an essential role in osteoarthritis (OA) progression. Recent studies have shown that snoRNA-derived RNA fragments (sdRNAs) are novel regulators of post-transcriptional gene expression. However, the expression profiles and their role in post-transcriptional gene regulation in chondrocyte senescence and OA progression is unknown. Here, we determined sdRNAs expression profile and explored sdRNA-D43 role in OA and its mechanism.

Methods: We used qPCR arrays to determine sdRNAs expression in the chondrocytes of areas undamaged and damaged of the three knee OA samples. SdRNA-D43 expression was determined using quantitative reverse transcription-polymerase chain reaction and in situ hybridization. Then, bioinformatics analysis was conducted on the target genes that might be silenced by sdRNA-D43. Primary chondrocytes of damaged regions of knee OA samples were transfected with a sdRNA-D43 inhibitor or mimic to determine their functions, including in relation to mitophagy and chondrocyte senescence. Argonaute2-RNA immunoprecipitation and luciferase reporter assays were conducted to determine the target gene of sdRNA-D43. In a rat OA model induced by monosodium iodoacetate, adeno-associated virus sh-rat-sdRNA-D43 was injected into the knee joint cavity to assess its in vivo effects.

Results: sdRNA-D43 expression were upregulated in damaged areas of knee OA cartilage with increased senescent chondrocytes. sdRNA-D43 inhibited mitophagy and promoted chondrocytes senescence during OA progression. Mechanistically, sdRNA-D43 silenced the expression of both NRF1 and WIPI2 by binding to their 3'-UTR in an Argonaute2‑dependent manner, which inhibited PINK1/Parkin-mediated pathway. Additionally, injection of AAV-sh-sdRNA-D43 alleviated the progression of OA in a monosodium iodoacetate-induced rat model.

Conclusion: Our results reveal an important role for a novel sdRNA-D43 in OA progression. sdRNA-D43 improves chondrocyte senescence by negatively regulating PINK1/Parkin-mediated mitophagy pathway via dual-targeting NRF1 and WIPI2, which provide a potential therapeutic strategy for OA treatment.

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