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

被引：0

作者：

Deng, Zengfa ^{[1
,3
,4
,5
]}

Li, Changzhao ^{[2
,3
,6
]}

Hu, Shu ^{[4
,5
]}

Zhong, Yanlin ^{[1
,3
]}

Li, Wei ^{[1
,3
]}

Lin, Zhencan ^{[1
,3
]}

Mo, Xiaolin ^{[1
,3
]}

Li, Ming ^{[1
,3
]}

Xu, Dongliang ^{[2
,3
]}

Long, Dianbo ^{[1
,3
]}

Mao, Guping ^{[1
,3
]}

Kang, Yan ^{[1
,3
]}

机构：

[1] Sun Yat Sen Univ, Affiliated Hosp 1, Dept Sports Med, Guangzhou, Guangdong, Peoples R China

[2] Sun Yat Sen Univ, Affiliated Hosp 1, Dept Joint Surg, Guangzhou, Guangdong, Peoples R China

[3] Sun Yat Sen Univ, Affiliated Hosp 1, Guangdong Prov Key Lab Orthoped & Traumatol, Guangzhou, Guangdong, Peoples R China

[4] Southern Med Univ, Affiliated Hosp 3, Ctr Orthoped Surg, Dept Joint Surg & Sports Med, Guangzhou, Peoples R China

[5] Southern Med Univ, Sch Clin Med 3, Guangzhou, Peoples R China

[6] Gen Hosp Southern Theater Command, Dept Orthopaed, Guangzhou, Peoples R China

来源：

CELL COMMUNICATION AND SIGNALING | 2025年 / 23卷 / 01期

关键词：

sdRNA-D43; snoRNA; Osteoarthritis; Chondrocyte senescence; Mitophagy; AUTOPHAGY; PROTECTS;

D O I：

10.1186/s12964-024-01975-2

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

BackgroundChondrocyte 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.MethodsWe 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.ResultssdRNA-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.ConclusionOur 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.

引用

页数：21