Abstract
Rheumatoid arthritis (RA) is an inflammatory autoimmune disease, and RA interstitial lung disease (ILD) is a severe complication of RA. This investigation aims to determine the effect and underlying mechanism of osthole (OS), which could be extracted from Cnidium, Angelica, and Citrus plants and evaluate the role of transglutaminase 2 (TGM2) in RA and RA-ILD. In this work, OS downregulated TGM2 to exert its additive effect with methotrexate and suppress the proliferation, migration, and invasion of RA-fibroblast-like synoviocytes (FLS) by attenuating NF-κB signaling, resulting in the suppression of RA progression. Interestingly, WTAP-mediated N6-methyladenosine modification of TGM2 and Myc-mediated WTAP transcription cooperatively contributed to the formation of a TGM2/Myc/WTAP-positive feedback loop through upregulating NF-κB signaling. Moreover, OS could downregulate the activation of the TGM2/Myc/WTAP-positive feedback circuit. Furthermore, OS restrained the proliferation and polarization of M2 macrophages to inhibit the aggregation of lung interstitial CD11b+ macrophages, and the effectiveness and non-toxicity of OS in suppressing RA and RA-ILD progression were verified in vivo. Finally, bioinformatics analyses validated the importance and the clinical significance of the OS-regulated molecular network. Taken together, our work emphasized OS as an effective drug candidate and TGM2 as a promising target for RA and RA-ILD treatment.
Published Version (Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.