PMID- 33408787 OWN - NLM STAT- MEDLINE DCOM- 20210816 LR - 20210816 IS - 1838-7640 (Electronic) IS - 1838-7640 (Linking) VI - 11 IP - 4 DP - 2021 TI - Novel role of circRSU1 in the progression of osteoarthritis by adjusting oxidative stress. PG - 1877-1900 LID - 10.7150/thno.53307 [doi] AB - Osteoarthritis (OA), characterized as an end-stage syndrome caused by risk factors accumulated with age, significantly impacts quality of life in the elderly. Circular RNAs (circRNAs) are receiving increasing attention regarding their role in OA progression and development; however, their role in the regulation of age-induced and oxidative stress-related OA remains unclear. Methods: Herein, we explored oxidative stress in articular cartilage obtained from patients of different ages. The presence of circRSU1 was detected using RNA sequencing of H(2)O(2)-stimulated primary human articular chondrocytes (HCs), and validated in articular cartilage and HCs using fluorescence in situ hybridization (FISH) staining. miR-93-5p and mitogen-activated protein kinase kinase kinase 8 (MAP3K8) were identified as interactive circRSU1 partners based on annotation and target prediction databases, and their associations were identified through dual-luciferase reporter analysis. The effect of the circRSU1-miR-93-5p-MAP3K8 axis on HCs was confirmed using western blot, quantitative real-time PCR (qRT-PCR), enzyme-linked immunosorbent assay (ELISA), immunofluorescence, and reactive oxygen species (ROS) analyses. CircRSU1 and its mutant were ectopically expressed in mice to assess their effects in destabilization of the medial meniscus (DMM) in mice. Results: We found a marked upregulation of circRSU1 in H(2)O(2)-treated HCs and OA articular cartilage from elderly individuals. circRSU1 was induced by IL-1beta and H(2)O(2) stimulation, and it subsequently regulated oxidative stress-triggered inflammation and extracellular matrix (ECM) maintenance in HCs, by modulating the MEK/ERK1/2 and NF-kappaB cascades. Ectopic expression of circRSU1 in mouse joints promoted the production of ROS and loss of ECM, which was rescued by mutation of the mir-93-5p target sequence in circRSU1. Conclusion: We identified a circRSU1-miR-93-5p-MAP3K8 axis that modulates the progression of OA via oxidative stress regulation, which could serve as a potential target for OA therapy. CI - (c) The author(s). FAU - Yang, Yute AU - Yang Y AD - Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine. AD - Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province. FAU - Shen, Panyang AU - Shen P AD - Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine. AD - Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province. FAU - Yao, Teng AU - Yao T AD - Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine. AD - Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province. FAU - Ma, Jun AU - Ma J AD - Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine. AD - Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province. FAU - Chen, Zizheng AU - Chen Z AD - Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine. AD - Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province. FAU - Zhu, Jinjin AU - Zhu J AD - Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine. AD - Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province. FAU - Gong, Zhe AU - Gong Z AD - Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine. AD - Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province. FAU - Shen, Shuying AU - Shen S AD - Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine. AD - Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province. FAU - Fang, Xiangqian AU - Fang X AD - Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine. AD - Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210101 PL - Australia TA - Theranostics JT - Theranostics JID - 101552395 RN - 0 (Biomarkers) RN - 0 (MIRN93 microRNA, human) RN - 0 (MicroRNAs) RN - 0 (Proto-Oncogene Proteins) RN - 0 (RNA, Circular) RN - 0 (Transcription Factors) RN - 148412-92-4 (RSU1 protein, human) RN - EC 2.7.11.25 (MAP Kinase Kinase Kinases) RN - EC 2.7.11.25 (MAP3K8 protein, human) SB - IM MH - Animals MH - Apoptosis MH - Biomarkers/metabolism MH - Cartilage, Articular/metabolism/*pathology MH - Cell Proliferation MH - Cells, Cultured MH - Gene Expression Regulation MH - Humans MH - MAP Kinase Kinase Kinases/genetics/*metabolism MH - Male MH - Mice MH - Mice, Inbred C57BL MH - MicroRNAs/*genetics MH - Osteoarthritis/genetics/metabolism/*pathology MH - *Oxidative Stress MH - Proto-Oncogene Proteins/genetics/*metabolism MH - RNA, Circular/*genetics MH - Transcription Factors/*genetics PMC - PMC7778608 OTO - NOTNLM OT - MAP3K8 OT - circRSU1 OT - osteoarthritis OT - oxidative stress COIS- Competing Interests: The authors have declared that no competing interest exists. EDAT- 2021/01/08 06:00 MHDA- 2021/08/17 06:00 PMCR- 2021/01/01 CRDT- 2021/01/07 06:06 PHST- 2020/09/15 00:00 [received] PHST- 2020/11/19 00:00 [accepted] PHST- 2021/01/07 06:06 [entrez] PHST- 2021/01/08 06:00 [pubmed] PHST- 2021/08/17 06:00 [medline] PHST- 2021/01/01 00:00 [pmc-release] AID - thnov11p1877 [pii] AID - 10.7150/thno.53307 [doi] PST - epublish SO - Theranostics. 2021 Jan 1;11(4):1877-1900. doi: 10.7150/thno.53307. eCollection 2021.