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Novel NFκB Inhibitor SC75741 Mitigates Chondrocyte Degradation and Prevents Activated Fibroblast Transformation by Modulating miR-21/GDF-5/SOX5 Signaling

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Department of Orthopaedics, School of Medicine, College of Medicine, Taipei Medical University, Taipei City 110, Taiwan
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Department of Orthopaedics, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan
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Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei City 110, Taiwan
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Department of Medical Research & Education, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, Taiwan
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School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei City 110, Taiwan
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Division of Periodontics, Department of Dentistry, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, Taiwan
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Department of Medical Laboratory Science and Biotechnology, Yuanpei University of Medical Technology, Hsinchu City 30015, Taiwan
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Department of Pathology, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, Taiwan
*
Authors to whom correspondence should be addressed.
Academic Editor: Elizabeth W. Bradley
Int. J. Mol. Sci. 2021, 22(20), 11082; https://doi.org/10.3390/ijms222011082
Received: 12 September 2021 / Revised: 4 October 2021 / Accepted: 9 October 2021 / Published: 14 October 2021
(This article belongs to the Special Issue Osteoarthritis 2.0: From Molecular Pathways to Therapeutic Advances)
Osteoarthritis (OA) is a common articular disease manifested by the destruction of cartilage and compromised chondrogenesis in the aging population, with chronic inflammation of synovium, which drives OA progression. Importantly, the activated synovial fibroblast (AF) within the synovium facilitates OA through modulating key molecules, including regulatory microRNAs (miR’s). To understand OA associated pathways, in vitro co-culture system, and in vivo papain-induced OA model were applied for this study. The expression of key inflammatory markers both in tissue and blood plasma were examined by qRT-PCR, western blot, immunohistochemistry, enzyme-linked immunosorbent assay (ELISA) and immunofluorescence assays. Herein, our result demonstrated, AF-activated human chondrocytes (AC) exhibit elevated NFκB, TNF-α, IL-6, and miR-21 expression as compared to healthy chondrocytes (HC). Importantly, AC induced the apoptosis of HC and inhibited the expression of chondrogenesis inducers, SOX5, TGF-β1, and GDF-5. NFκB is a key inflammatory transcription factor elevated in OA. Therefore, SC75741 (an NFκB inhibitor) therapeutic effect was explored. SC75741 inhibits inflammatory profile, protects AC-educated HC from apoptosis, and inhibits miR-21 expression, which results in the induced expression of GDF-5, SOX5, TGF-β1, BMPR2, and COL4A1. Moreover, ectopic miR-21 expression in fibroblast-like activated chondrocytes promoted osteoblast-mediated differentiation of osteoclasts in RW264.7 cells. Interestingly, in vivo study demonstrated SC75741 protective role, in controlling the destruction of the articular joint, through NFκB, TNF-α, IL-6, and miR-21 inhibition, and inducing GDF-5, SOX5, TGF-β1, BMPR2, and COL4A1 expression. Our study demonstrated the role of NFκB/miR-21 axis in OA progression, and SC75741’s therapeutic potential as a small-molecule inhibitor of miR-21/NFκB-driven OA progression. View Full-Text
Keywords: osteoarthritis (OA); NFκB inflammatory circuit; miR-21/GDF-5/SOX5 signaling; NFκB inhibitor; therapeutics osteoarthritis (OA); NFκB inflammatory circuit; miR-21/GDF-5/SOX5 signaling; NFκB inhibitor; therapeutics
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MDPI and ACS Style

Weng, P.-W.; Yadav, V.K.; Pikatan, N.W.; Fong, I.-H.; Lin, I.-H.; Yeh, C.-T.; Lee, W.-H. Novel NFκB Inhibitor SC75741 Mitigates Chondrocyte Degradation and Prevents Activated Fibroblast Transformation by Modulating miR-21/GDF-5/SOX5 Signaling. Int. J. Mol. Sci. 2021, 22, 11082. https://doi.org/10.3390/ijms222011082

AMA Style

Weng P-W, Yadav VK, Pikatan NW, Fong I-H, Lin I-H, Yeh C-T, Lee W-H. Novel NFκB Inhibitor SC75741 Mitigates Chondrocyte Degradation and Prevents Activated Fibroblast Transformation by Modulating miR-21/GDF-5/SOX5 Signaling. International Journal of Molecular Sciences. 2021; 22(20):11082. https://doi.org/10.3390/ijms222011082

Chicago/Turabian Style

Weng, Pei-Wei, Vijesh K. Yadav, Narpati W. Pikatan, Iat-Hang Fong, I-Hsin Lin, Chi-Tai Yeh, and Wei-Hwa Lee. 2021. "Novel NFκB Inhibitor SC75741 Mitigates Chondrocyte Degradation and Prevents Activated Fibroblast Transformation by Modulating miR-21/GDF-5/SOX5 Signaling" International Journal of Molecular Sciences 22, no. 20: 11082. https://doi.org/10.3390/ijms222011082

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