Interleukin-23 Mediates Osteoclastogenesis in Collagen-Induced Arthritis by Modulating MicroRNA-223

• Published in: International journal of molecular sciences 2022-09, Vol.23 (17), p.9718
• Main Authors: Chen, Shih-Yao, Tsai, Ting-Chien, Li, Yuan-Tsung, Ding, Yun-Chiao, Wang, Chung-Teng, Hsieh, Jeng-Long, Wu, Chao-Liang, Wu, Po-Ting, Shiau, Ai-Li
• Format: Article
• Language: English
• Subjects: Arthritis; Binding; Binding sites; Bone marrow; Cartilage; Chemical compounds; Collagen; collagen-induced arthritis; Cytokines; Differentiation; Gene regulation; Hyperplasia; In vivo methods and tests; Interleukin 23; Joint diseases; Macrophages; microRNA-223; MicroRNAs; miRNA; Osteoclastogenesis; Pathogenesis; Pharmacology; Rheumatoid arthritis; Stat4 protein; Stimulation; Synovium; Transcription factors; Transducers; Tumor necrosis factor-TNF
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23179718

Interleukin-23 (IL-23) plays a pivotal role in rheumatoid arthritis (RA). IL-23 and microRNA-223 (miR-223) are both up-regulated and mediate osteoclastogenesis in mice with collagen-induced arthritis (CIA). The aim of this study was to examine the association between IL-23 and miR-223 in contributing to osteoclastogenesis and arthritis. Levels of IL-23p19 in joints of mice with CIA were determined. Lentiviral vectors expressing short hairpin RNA (shRNA) targeting IL-23p19 and lisofylline (LSF) were injected intraperitoneally into arthritic mice. Bone marrow-derived macrophages (BMMs) were treated with signal transducers and activators of transcription 4 (STAT4) specific shRNA and miR-223 sponge carried by lentiviral vectors in response to IL-23 stimulation. Treatment responses were determined by evaluating arthritis scores and histopathology in vivo, and detecting osteoclast differentiation and miR-223 levels in vitro. The binding of STAT4 to the promoter region of primary miR-223 (pri-miR-223) was determined in the Raw264.7 cell line. IL-23p19 expression was increased in the synovium of mice with CIA. Silencing IL-23p19 and inhibiting STAT4 activity ameliorates arthritis by reducing miR-223 expression. BMMs from mice in which STAT4 and miR-223 were silenced showed decreased osteoclast differentiation in response to IL-23 stimulation. IL-23 treatment increased the expression of miR-223 and enhanced the binding of STAT4 to the promoter of pri-miR-223. This study is the first to demonstrate that IL-23 promotes osteoclastogenesis by transcriptional regulation of miR-223 in murine macrophages and mice with CIA. Furthermore, our data indicate that LSF, a selective inhibitor of STAT4, should be an ideal therapeutic agent for treating RA through down-regulating miR-223-associated osteoclastogenesis.