Liangyu Chen, Junfeng Wu, Tao Zhou, Zilin Zou, Qinwei Cheng, Dalin Chen, Honghao Li, Panpan Yang, Chengliang Yang, Hong Wang, Kai Li
FSCN1 was significantly increased in RA synovium and predominantly localized to PDPN-positive FLS (P<0.001). FSCN1 overexpression enhanced F-actin remodeling, FLS migration, invasion, proliferation, and inflammatory activation, and exacerbated synovitis and cartilage damage in arthritis mouse models (P<0.0026). Conversely, FLS-specific FSCN1 ablation reduced knee swelling, pain-related behavior, synovial inflammation, and OARSI scores in arthritis mouse models (P<0.0196). Mechanistically, FSCN1 promoted F-actin fiber formation, spatially sequestered TRIM38, inhibited TRIM38-mediated IGF2BP1 ubiquitination, and sustained PI3K-AKT/NF-κB signaling. The FSCN1 inhibitors imipramine and NP-G2-044 suppressed FLS activation and alleviated arthritis pathology in mice (P<0.001).
OBJECTIVE: Fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA) synovium acquire a unique aggressive phenotype and produce cytokines that perpetuate inflammation and proteases that contribute to cartilage destruction. Actin bundling protein Fascin-1 (FSCN1) is involved in FLS migration and invasion, but its role and mechanism in FLS phenotypic activation remain unclear.
METHODS: FSCN1 expression was analyzed in the synovium from healthy controls (n=6), RA (n=6) and osteoarthritis (n=6) patients with written informed consent obtained prior to sample collection, as well as synovium from control (n=6) and arthritic mice (n=6). Transcriptome profiling, RNA immunoprecipitation sequencing and mass spectrometry analysis were performed to determine the underlying mechanism. FLS-specific FSCN1 knockout, FSCN1 intra-articular overexpression mice, and FSCN1 inhibitors were utilized to characterize the role and therapeutic potential of FSCN1 in experimental arthritis (n=5-8).
RESULTS: FSCN1 was significantly increased in RA synovium and predominantly localized to PDPN-positive FLS (P<0.001). FSCN1 overexpression enhanced F-actin remodeling, FLS migration, invasion, proliferation, and inflammatory activation, and exacerbated synovitis and cartilage damage in arthritis mouse models (P<0.0026). Conversely, FLS-specific FSCN1 ablation reduced knee swelling, pain-related behavior, synovial inflammation, and OARSI scores in arthritis mouse models (P<0.0196). Mechanistically, FSCN1 promoted F-actin fiber formation, spatially sequestered TRIM38, inhibited TRIM38-mediated IGF2BP1 ubiquitination, and sustained PI3K-AKT/NF-κB signaling. The FSCN1 inhibitors imipramine and NP-G2-044 suppressed FLS activation and alleviated arthritis pathology in mice (P<0.001).
DISCUSSION: Pharmacological inhibition of FSCN1 restrains synovial inflammation and joint destruction by suppressing the aggressive phenotype change of FLS, representing a promising therapeutic strategy against RA.