title: Anti-invasive effects of celastrol in hypoxia-induced fibroblast-like synoviocyte through suppressing of HIF-1α/CXCR4 signaling pathway.
abstract: Rheumatoid arthritis (RA) joints are in a hypoxic condition. Hypoxia-induced migration and invasion of fibroblast-like synoviocytes (FLSs) are considered to play a critical role in the pathogenesis of RA. Among the key genes upregulated by hypoxia-inducible factor-1α (HIF-1α), CXC chemokine receptor 4 (CXCR4) plays an important role in FLS migration and invasion. Our previous studies have shown that celastrol exerts anti-arthritic effects by inhibiting FLS migration and invasion under normoxic conditions. However, the effect and molecular mechanisms underlying the effect of celastrol on hypoxia-induced FLS migration and invasion are poorly understood. In the present study, we assessed the effect of celastrol on hypoxia-induced FLS migration and invasion. Results showed that celastrol suppressed hypoxia-induced FLS migration and invasion. In addition, we also found that celastrol inhibited hypoxia-induced CXCR4 expression at both the mRNA and the protein levels in RA-FLSs. Meanwhile, it is revealed that celastrol inhibited the transcriptional activity of CXCR4 under hypoxic conditions by suppressing the binding activity of HIF-1α in the CXCR4 promoter, and blocked hypoxia-induced accumulation of nuclear HIF-1α. Furthermore, treatment with HIF-1α inhibitor reduced the hypoxia-induced expression and transcriptional activity of CXCR4. In conclusion, our results indicate that celastrol inhibits hypoxia-induced migration and invasion via suppression of HIF-1α mediated CXCR4 expression in FLSs under hypoxic conditions. These results provide a strong rationale for further testing and validation of the use of celastrol as a new alternative for using in the treatment of RA.
authors.affiliation: Department of Rheumatology, Clinical Medical College, Yangzhou University, Yangzhou 225000, China.
authors.forename: Guo-qing
authors.initials: GQ
authors.lastname: Li
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Ya-yun
authors.initials: YY
authors.lastname: Qian
authors.forename: Yao-dong
authors.initials: YD
authors.lastname: Zhu
authors.forename: Shi-yu
authors.initials: SY
authors.lastname: Guo
authors.forename: Masataka
authors.initials: M
authors.lastname: Sunagawa
authors.forename: Tadashi
authors.initials: T
authors.lastname: Hisamitsu
authors.forename: Yan-qing
authors.initials: YQ
authors.lastname: Liu
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053978:Pentacyclic Triterpenes; D034741:RNA, Small Interfering / Q000235:genetics; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013583:Synovial Membrane / Q000166:cytology; D014315:Triterpenes / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; C527276:CXCR4 protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D053978:Pentacyclic Triterpenes; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4; D014315:Triterpenes; C050414:celastrol
keywords: CXCR4; Celastrol; Fibroblast-like synoviocyte; HIF-1α; Invasion; Rheumatoid arthritis