Cytokine · 2025
Amphiregulin activation upon ZEB1 loss promotes pro-inflammatory activation and osteoclastic differentiation of macrophages in rheumatoid arthritis.
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Zhang Boke, Lu Yachun, Lu Feng, Li Tingting, Gao Junling, Sun Tai
Аннотация
BACKGROUND: Rheumatoid arthritis (RA) is a multifactorial autoimmune disease primarily affecting the joints. This study, grounded on bioinformatics insights, investigates the biological effects of zinc finger E-box binding homeobox 1 (ZEB1) in the context of RA and delves into the functional mechanism.
METHODS: A murine model of RA was induced by collagen type II challenge. ZEB1 expression in the bone tissue of RA mice was determined by immunohistochemistry or RT-qPCR. Transcriptional targets of ZEB1 were predicted using bioinformatics. Gain-of-function assays of ZEB1 and amphiregulin (AREG) were performed to analyze their roles in arthritis severity, bone loss, inflammation, and macrophage polarization in mice. Furthermore, the pro-inflammatory activation and osteoclastic differentiation of mouse RAW264.7 macrophages upon ZEB1 and AREG overexpression were determined for in vitro verification.
RESULTS: ZEB1 was poorly expressed in the modeled mice. Its upregulation alleviated arthritis severity, reduced serum levels of inflammatory cytokines, alleviated bone erosion and cartilage loss, and reduced M1 polarization of macrophages in mice. In vitro, ZEB1 upregulation reduced pro-inflammatory activation and osteoclastic differentiation of mouse RAW264.7 macrophages after specific stimuli. AREG was identified as a transcriptional target of ZEB1, highly expressed in RA. The additional overexpression of AREG counteracted the RA-ameliorating effect of ZEB1 in mice and restored inflammatory activation and osteoclastogenesis of RAW264.7 cells in vitro.
CONCLUSION: This study demonstrates that ZEB1 represses AREG transcription, thus alleviating pro-inflammatory activation and osteoclastic differentiation of macrophages in the context of RA.
METHODS: A murine model of RA was induced by collagen type II challenge. ZEB1 expression in the bone tissue of RA mice was determined by immunohistochemistry or RT-qPCR. Transcriptional targets of ZEB1 were predicted using bioinformatics. Gain-of-function assays of ZEB1 and amphiregulin (AREG) were performed to analyze their roles in arthritis severity, bone loss, inflammation, and macrophage polarization in mice. Furthermore, the pro-inflammatory activation and osteoclastic differentiation of mouse RAW264.7 macrophages upon ZEB1 and AREG overexpression were determined for in vitro verification.
RESULTS: ZEB1 was poorly expressed in the modeled mice. Its upregulation alleviated arthritis severity, reduced serum levels of inflammatory cytokines, alleviated bone erosion and cartilage loss, and reduced M1 polarization of macrophages in mice. In vitro, ZEB1 upregulation reduced pro-inflammatory activation and osteoclastic differentiation of mouse RAW264.7 macrophages after specific stimuli. AREG was identified as a transcriptional target of ZEB1, highly expressed in RA. The additional overexpression of AREG counteracted the RA-ameliorating effect of ZEB1 in mice and restored inflammatory activation and osteoclastogenesis of RAW264.7 cells in vitro.
CONCLUSION: This study demonstrates that ZEB1 represses AREG transcription, thus alleviating pro-inflammatory activation and osteoclastic differentiation of macrophages in the context of RA.