Novel nfκb inhibitor sc75741 mitigates chondrocyte degradation and prevents activated fibroblast transformation by modulating mir‐21/gdf‐5/sox5 signaling

Pei Wei Weng, Vijesh Kumar Yadav, Narpati Wesa Pikatan, Iat Hang Fong, I. Hsin Lin, Chi Tai Yeh, Wei Hwa Lee

研究成果: 雜誌貢獻文章同行評審

摘要

Osteoarthritis (OA) is a common articular disease manifested by the destruction of cartilage and compromised chondrogenesis in the aging population, with chronic inflammation of syn-ovium, 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, en-zyme‐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 apop-tosis 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 in-hibitor) therapeutic effect was explored. SC75741 inhibits inflammatory profile, protects AC‐edu-cated 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.

原文英語
文章編號11082
期刊International journal of molecular sciences
22
發行號20
DOIs
出版狀態已發佈 - 十月 1 2021

ASJC Scopus subject areas

  • 催化
  • 分子生物學
  • 光譜
  • 電腦科學應用
  • 物理與理論化學
  • 有機化學
  • 無機化學

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